8-144316558-GC-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM4 PP5_Moderate

The NM_012079.6(DGAT1):c.1462del(p.Ala488ProfsTer226) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,439,944 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. A488A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DGAT1 NM_012079.6 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: -0.408

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Frameshift in the end of transcript resulting in stoplost. Downstream stopcodon found after 1268 codons.
• PP5: Variant 8-144316558-GC-G is Pathogenic according to our data. Variant chr8-144316558-GC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 504005.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DGAT1	NM_012079.6	c.1462del	p.Ala488ProfsTer226	frameshift_variant	17/17	ENST00000528718.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DGAT1	ENST00000528718.6	c.1462del	p.Ala488ProfsTer226	frameshift_variant	17/17	1	NM_012079.6	P1
DGAT1	ENST00000332324.5	c.*17del		3_prime_UTR_variant	10/10	5
DGAT1	ENST00000524965.5	n.1097del		non_coding_transcript_exon_variant	12/12	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1439944 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 714084

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 03, 2021

Frameshift variant predicted to result in protein truncation, as the last 1 amino acids are replaced with 225 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31778854) -

Congenital diarrhea 7 with exudative enteropathy Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 30, 2022

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554847009; hg19: chr8-145540221;