rs2792751

Positions:

• chr10-112180571-T-C
• chr10-112180571-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001244949.2(GPAM):​c.127A>G​(p.Ile43Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.733 in 1,608,874 control chromosomes in the GnomAD database, including 434,741 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.77 (45662 hom., cov: 32)
  • Exomes 𝑓: 0.73 (389079 hom.)
• Consequence: GPAM NM_001244949.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.25

Genes affected

GPAM (HGNC:24865): (glycerol-3-phosphate acyltransferase, mitochondrial) This gene encodes a mitochondrial enzyme which prefers saturated fatty acids as its substrate for the synthesis of glycerolipids. This metabolic pathway's first step is catalyzed by the encoded enzyme. Two forms for this enzyme exist, one in the mitochondria and one in the endoplasmic reticulum. Two alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, Oct 2011]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.5698847E-7).
• BP6: Variant 10-112180571-T-C is Benign according to our data. Variant chr10-112180571-T-C is described in ClinVar as [Benign]. Clinvar id is 1285804.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.919 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPAM	NM_001244949.2	c.127A>G	p.Ile43Val	missense_variant	4/22	ENST00000348367.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPAM	ENST00000348367.9	c.127A>G	p.Ile43Val	missense_variant	4/22	1	NM_001244949.2	P1
GPAM	ENST00000369425.5	c.127A>G	p.Ile43Val	missense_variant	4/19	1
GPAM	ENST00000480130.5	n.464A>G		non_coding_transcript_exon_variant	4/4	2
GPAM	ENST00000498541.1	n.332A>G		non_coding_transcript_exon_variant	4/4	3

Frequencies

GnomAD3 genomes AF: 0.767 AC: 116644 AN: 151988 Hom.: 45610 Cov.: 32

Gnomad AFR AF: 0.927

Gnomad AMI AF: 0.571

Gnomad AMR AF: 0.699

Gnomad ASJ AF: 0.580

Gnomad EAS AF: 0.736

Gnomad SAS AF: 0.830

Gnomad FIN AF: 0.669

Gnomad MID AF: 0.576

Gnomad NFE AF: 0.713

Gnomad OTH AF: 0.728

GnomAD3 exomes AF: 0.734 AC: 184441 AN: 251212 Hom.: 68492 AF XY: 0.731 AC XY: 99271 AN XY: 135786

Gnomad AFR exome AF: 0.931

Gnomad AMR exome AF: 0.726

Gnomad ASJ exome AF: 0.580

Gnomad EAS exome AF: 0.725

Gnomad SAS exome AF: 0.828

Gnomad FIN exome AF: 0.676

Gnomad NFE exome AF: 0.711

Gnomad OTH exome AF: 0.715

GnomAD4 exome AF: 0.729 AC: 1061827 AN: 1456768 Hom.: 389079 Cov.: 35 AF XY: 0.729 AC XY: 528740 AN XY: 725044

Gnomad4 AFR exome AF: 0.937

Gnomad4 AMR exome AF: 0.722

Gnomad4 ASJ exome AF: 0.571

Gnomad4 EAS exome AF: 0.753

Gnomad4 SAS exome AF: 0.817

Gnomad4 FIN exome AF: 0.677

Gnomad4 NFE exome AF: 0.721

Gnomad4 OTH exome AF: 0.734

GnomAD4 genome AF: 0.768 AC: 116755 AN: 152106 Hom.: 45662 Cov.: 32 AF XY: 0.765 AC XY: 56868 AN XY: 74362

Gnomad4 AFR AF: 0.927

Gnomad4 AMR AF: 0.698

Gnomad4 ASJ AF: 0.580

Gnomad4 EAS AF: 0.737

Gnomad4 SAS AF: 0.829

Gnomad4 FIN AF: 0.669

Gnomad4 NFE AF: 0.713

Gnomad4 OTH AF: 0.732

Alfa AF: 0.709 Hom.: 88307

Bravo AF: 0.772

TwinsUK AF: 0.731 AC: 2711

ALSPAC AF: 0.720 AC: 2774

ESP6500AA AF: 0.926 AC: 4081

ESP6500EA AF: 0.707 AC: 6076

ExAC AF: 0.742 AC: 90130

Asia WGS AF: 0.805 AC: 2797 AN: 3478

EpiCase AF: 0.702

EpiControl AF: 0.697

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 10, 2019	This variant is associated with the following publications: (PMID: 29083407, 32640185) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	1.4
DANN	Benign	0.14
DEOGEN2	Benign	0.048	T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.071	T;T
MetaRNN	Benign	7.6e-7	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-1.6	N;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.48	T
PROVEAN	Benign	0.15	N;N
REVEL	Benign	0.042
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.028
MPC		0.23
ClinPred		0.0000096	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.021
gMVP		0.19

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: rs2792751; hg19: chr10-113940329; COSMIC: COSV62081535;