NM_012079.6:c.751+2T>G

Variant names:

• chr8-144318093-A-C
• rs148665132
• NM_012079.6:c.751+2T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_012079.6(DGAT1):​c.751+2T>G variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000727 in 1,375,652 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: not found (cov: 33)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: DGAT1 NM_012079.6 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.06
• Publications: 0 publications found

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 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-C is Pathogenic according to our data. Variant chr8-144318093-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 2837131.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DGAT1	NM_012079.6	c.751+2T>G		splice_donor_variant, intron_variant	Intron 8 of 16	ENST00000528718.6	NP_036211.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DGAT1	ENST00000528718.6	c.751+2T>G		splice_donor_variant, intron_variant	Intron 8 of 16	1	NM_012079.6	ENSP00000482264.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.27e-7 AC: 1 AN: 1375652 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 674938

African (AFR) AF: 0.00 AC: 0 AN: 30762

American (AMR) AF: 0.00 AC: 0 AN: 31596

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20334

East Asian (EAS) AF: 0.00 AC: 0 AN: 39002

South Asian (SAS) AF: 0.00 AC: 0 AN: 72074

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49330

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5348

European-Non Finnish (NFE) AF: 9.34e-7 AC: 1 AN: 1070594

Other (OTH) AF: 0.00 AC: 0 AN: 56612

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Feb 14, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. 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). Experimental studies have shown that disruption of this splice site affects DGAT1 function (PMID: 23114594). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. 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 not present in population databases (gnomAD no frequency). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Benign	-0.29
CADD	Pathogenic	27
DANN	Benign	0.97
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		2.1
GERP RS		3.5
Mutation Taster		=9/91	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.36		Position offset: 33
DS_DL_spliceai		0.99		Position offset: 2

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

Other links and lift over

dbSNP: rs148665132; hg19: chr8-145541756;