chr8-144318093-A-G

Position:

chr8-144318093-A-G

Variant summary

Our verdict is Pathogenic. Variant got 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:10

Conservation

PhyloP100: 2.06

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 links:

DGAT1 (HGNC:):

DGAT1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.05044308 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 id is 139512.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DGAT1	NM_012079.6 linkuse as main transcript	c.751+2T>C		splice_donor_variant, intron_variant		ENST00000528718.6	NP_036211.2	O75907

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DGAT1	ENST00000528718.6 linkuse as main transcript	c.751+2T>C		splice_donor_variant, intron_variant		1	NM_012079.6	ENSP00000482264.1		O75907

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

GnomAD3 exomes

AF:

0.000130

AC:

AN:

184594

Hom.:

AF XY:

0.000123

AC XY:

AN XY:

97422

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 SAS 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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000949

Gnomad4 ASJ exome

AF:

0.00438

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000215

Gnomad4 OTH exome

AF:

0.000477

GnomAD4 genome

AF:

0.000131

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00403

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

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:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Congenital diarrhea 7 with exudative enteropathy

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 20, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 01, 2017	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Elsea Laboratory, Baylor College of Medicine	Apr 01, 2020	- -
Pathogenic, criteria provided, single submitter	research	Aleixo Muise Laboratory, Hospital For Sick Children	Jul 05, 2024	PVS1;PM2;PM3;PP3;PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 03, 2012	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 08, 2024	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 protein 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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 20, 2024	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) -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 02, 2018

- -

DGAT1-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 20, 2024

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Benign

-0.22

CADD

Uncertain

DANN

Benign

0.97

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.96

GERP RS

3.5

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over