8-144316559-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_012079.6(DGAT1):c.1462G>A(p.Ala488Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000208 in 1,440,100 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). 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: 0.0000021 (0 hom.)
• Consequence: DGAT1 NM_012079.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.047652453).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DGAT1	NM_012079.6	c.1462G>A	p.Ala488Thr	missense_variant	17/17	ENST00000528718.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DGAT1	ENST00000528718.6	c.1462G>A	p.Ala488Thr	missense_variant	17/17	1	NM_012079.6	P1
DGAT1	ENST00000332324.5	c.*17G>A		3_prime_UTR_variant	10/10	5
DGAT1	ENST00000524965.5	n.1097G>A		non_coding_transcript_exon_variant	12/12	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000208 AC: 3 AN: 1440100 Hom.: 0 Cov.: 33 AF XY: 0.00000280 AC XY: 2 AN XY: 714192

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: 0.0000197

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000336

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000828 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 15, 2022

The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 488 of the DGAT1 protein (p.Ala488Thr). This variant has not been reported in the literature in individuals affected with DGAT1-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 1363716). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	16
Dann	Uncertain	1.0
DEOGEN2	Benign	0.063	T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.35	N
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.048	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	1.0	D;N
PrimateAI	Benign	0.32	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.0030	B
Vest4		0.11
MutPred		0.25		Gain of glycosylation at A488 (P = 0.0158);
MVP		0.22
ClinPred		0.57	D
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.059
gMVP		0.47

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: rs782022899; hg19: chr8-145540222;