chr8-144318305-TAGG-T

Position:

• chr8-144318305-TAGG-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PM4_Supporting PP5_Very_Strong

The NM_012079.6(DGAT1):​c.629_631del​(p.Ser210del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000117 in 1,612,540 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: DGAT1 NM_012079.6 inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 U:2
• Conservation: PhyloP100: 7.74

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 Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_012079.6. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 8-144318305-TAGG-T is Pathogenic according to our data. Variant chr8-144318305-TAGG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 548013.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	c.629_631del	p.Ser210del	inframe_deletion	7/17	ENST00000528718.6	NP_036211.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DGAT1	ENST00000528718.6	c.629_631del	p.Ser210del	inframe_deletion	7/17	1	NM_012079.6	ENSP00000482264	P1

Frequencies

GnomAD3 genomes AF: 0.0000921 AC: 14 AN: 152014 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000177

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000521 AC: 13 AN: 249596 Hom.: 0 AF XY: 0.0000517 AC XY: 7 AN XY: 135436

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000890

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000120 AC: 175 AN: 1460526 Hom.: 0 AF XY: 0.000122 AC XY: 89 AN XY: 726578

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000382

Gnomad4 NFE exome AF: 0.000150

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000921 AC: 14 AN: 152014 Hom.: 0 Cov.: 33 AF XY: 0.0000539 AC XY: 4 AN XY: 74246

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000177

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000253 Hom.: 0

Bravo AF: 0.000113

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5 Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital diarrhea 7 with exudative enteropathy Pathogenic:3 Uncertain:1

Uncertain significance, flagged submission	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 15, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 07, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Jul 30, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 30, 2022	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 09, 2021	Published functional studies demonstrate a damaging effect with reduced DGAT1 protein levels observed in cells transfected with DGAT1 gene with this variant (van Rijn et al., 2018); In-frame deletion of 1 amino acids in a non-repeat region; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31778854, 33144682, 33607125, 29604290) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 30, 2023	This variant, c.629_631del, results in the deletion of 1 amino acid(s) of the DGAT1 protein (p.Ser210del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs782577883, gnomAD 0.01%). This variant has been observed in individual(s) with protein-losing enteropathy (PMID: 29604290, 31778854, 33607125). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 548013). Studies have shown that this variant alters DGAT1 gene expression (PMID: 29604290). For these reasons, this variant has been classified as Pathogenic. -

See cases Uncertain:1

Uncertain significance, flagged submission

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Jun 24, 2020

ACMG classification criteria: PM2, PM4, PP3 -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs782577883; hg19: chr8-145541968;