8-144318093-A-G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong

The NM_012079.6(DGAT1):c.751+2T>C variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000106 in 1,527,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

DGAT1
NM_012079.6 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 2.06

Publications

7 publications found

Variant links:

Genes affected

DGAT1 (HGNC:2843): (diacylglycerol O-acyltransferase 1) This gene encodes an multipass transmembrane protein that functions as a key metabolic enzyme. The encoded protein catalyzes the conversion of diacylglycerol and fatty acyl CoA to triacylglycerol. This enzyme can also transfer acyl CoA to retinol. Activity of this protein may be associated with obesity and other metabolic diseases. [provided by RefSeq, Jul 2013]

DGAT1 Gene-Disease associations (from GenCC):

congenital diarrhea 7 with exudative enteropathy
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia, Ambry Genetics

DGAT1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.051124744 fraction of the gene. Cryptic splice site detected, with MaxEntScore 6.8, offset of 23, new splice context is: gagGTgcgg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 8-144318093-A-G is Pathogenic according to our data. Variant chr8-144318093-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 139512.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012079.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DGAT1	NM_012079.6	MANE Select	c.751+2T>C		splice_donor intron	N/A	NP_036211.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
DGAT1	ENST00000528718.6	TSL:1 MANE Select	c.751+2T>C	splice_donor intron	N/A	ENSP00000482264.1
DGAT1	ENST00000332324.5	TSL:5	c.676+168T>C	intron	N/A	ENSP00000332258.5
DGAT1	ENST00000524844.1	TSL:3	n.136+2T>C	splice_donor intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.000131

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00403

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000130

AC:

AN:

184594

AF XY:

0.000123

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000435

Gnomad ASJ exome

AF:

0.00484

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000227

Gnomad OTH exome

AF:

0.000465

GnomAD4 exome

AF:

0.000103

AC:

142

AN:

1375652

Hom.:

Cov.:

AF XY:

0.000101

AC XY:

AN XY:

674938

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30762

American (AMR)

AF:

0.0000949

AC:

AN:

31596

Ashkenazi Jewish (ASJ)

AF:

0.00438

AC:

AN:

20334

East Asian (EAS)

AF:

0.00

AC:

AN:

39002

South Asian (SAS)

AF:

0.00

AC:

AN:

72074

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49330

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5348

European-Non Finnish (NFE)

AF:

0.0000215

AC:

AN:

1070594

Other (OTH)

AF:

0.000477

AC:

AN:

56612

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000131

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41438

American (AMR)

AF:

0.000131

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00403

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000410

Hom.:

Bravo

AF:

0.000155

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000582

AC:

ExAC

AF:

0.000133

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Congenital diarrhea 7 with exudative enteropathy

Pathogenic:7

Jul 05, 2024

Aleixo Muise Laboratory, Hospital For Sick Children

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

PVS1;PM2;PM3;PP3;PP4

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 24, 2021

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 20, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.751+2T>C variant in DGAT1 has been reported in 6 individuals with congenital diarrheal disorders (CDD), all of whom carried the variant in the homozygous or compound heterozygous state, and segregated with disease in 3 affected siblings from 3 families (Haas 2012 PMID: 23114594, Yourshaw 2014, Niu 2015, Stephen 2016 PMID: 26883093, Schlegel 2018 PMID: 30095213, Ziats 2020 PMID: 31618753). It was also identified in 0.48% (19/3924) of Ashkenazi Jewish chromosomes by the gnomAD (http://gnomad.broadinstitute.org); however, this frequency is consistent with the fact that it is likely to be a founder variant in the Ashkenazi Jewish population. This variant has also been reported in ClinVar (Variation ID 139512). The c.751+2T>C variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and has been demonstrated to cause altered splicing leading to an abnormal or absent protein (Haas 2012 PMID: 23114594, ). In vitro functional studies provide some evidence that the altered splicing may impact protein stability (Haas 2012 PMID: 23114594, Schlegel 2018 PMID: 30095213). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive CDD. ACMG/AMP criteria applied: PVS1_Strong, PM3_Strong, PP1_Strong, PS3_Moderate.

Dec 03, 2012

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Apr 01, 2020

Elsea Laboratory, Baylor College of Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 01, 2017

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This mutation has been previously reported as disease-causing and was found in two affected individuals in our laboratory, including a homozygote and a compound hetrozygote. Both inidividuals had FTT, diarrhea, significant fat malabsorption. Heterozygotes are expected to be asymptomatic carriers.

not provided

Pathogenic:2

Jun 20, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect; specifically, cDNA analysis revealed exon 8 skipping leading to the deletion of 25 amino-acids from the MBOAT domain, and molecular analysis of the mutant allele indicated a total loss of function, with no detectable DGAT1 protein or activity produced (PMID: 23114594); Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 26883093, 23114594, 30095213, 31618753, 31589614)

Oct 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change affects a donor splice site in intron 8 of the DGAT1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs148665132, gnomAD 0.5%). Disruption of this splice site has been observed in individual(s) with congenital chronic diarrhea (PMID: 23114594, 26883093). It has also been observed to segregate with disease in related individuals. This variant is also known as g.13827T>C and g.145541756A>G. ClinVar contains an entry for this variant (Variation ID: 139512). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of this splice site affects DGAT1 function (PMID: 23114594). Studies have shown that disruption of this splice site results in skipping of exon 8, but is expected to preserve the integrity of the reading-frame (PMID: 23114594). For these reasons, this variant has been classified as Pathogenic.

Inborn genetic diseases

Pathogenic:1

Feb 02, 2018

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DGAT1-related disorder

Pathogenic:1

Mar 20, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The DGAT1 c.751+2T>C variant is predicted to disrupt the GT donor site and interfere with normal splicing. In the literature, this variant is also reported as 145541756 A>G, g.13827T>C, or rs148665132. This variant has been reported in the homozygous state in multiple individuals with congenital chronic diarrhea (Haas et al. 2012. PubMed ID: 23114594; Family 2, Stephen et al. 2016. PubMed ID: 26883093; Schlegel et al. 2018. PubMed ID: 30095213). This variant has also been shown to segregate with disease in the above reported families. Functional analyses have shown that this variant causes skipping of exon 8 and abolishes DGAT1 protein activity (Reported as 145541756 A>G, Haas et al. 2012. PubMed ID: 23114594). This variant is reported in 0.48% of alleles in individuals of Ashkenazi Jewish descent in gnomAD and is reported as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/139512/). Variants that disrupt the consensus splice donor site in DGAT1 are expected to be pathogenic. This variant is interpreted as pathogenic.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Benign

-0.22

CADD

Uncertain

(source)

DANN

Benign

0.97

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.96

PhyloP100

2.1

GERP RS

3.5

Mutation Taster

=9/91

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.96

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.54

Position offset: -21

DS_DL_spliceai

0.99

Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over