rs9835387

Positions:

• chr3-32140269-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_015141.4(GPD1L):​c.408C>T​(p.Asp136Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.137 in 1,613,640 control chromosomes in the GnomAD database, including 17,146 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2795 hom., cov: 32)
  • Exomes 𝑓: 0.13 (14351 hom.)
• Consequence: GPD1L NM_015141.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.37

Genes affected

GPD1L (HGNC:28956): (glycerol-3-phosphate dehydrogenase 1 like) The protein encoded by this gene catalyzes the conversion of sn-glycerol 3-phosphate to glycerone phosphate. The encoded protein is found in the cytoplasm, associated with the plasma membrane, where it binds the sodium channel, voltage-gated, type V, alpha subunit (SCN5A). Defects in this gene are a cause of Brugada syndrome type 2 (BRS2) as well as sudden infant death syndrome (SIDS). [provided by RefSeq, Jul 2010]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.26).
• BP6: Variant 3-32140269-C-T is Benign according to our data. Variant chr3-32140269-C-T is described in ClinVar as [Benign]. Clinvar id is 260571.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-32140269-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.37 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.295 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GPD1L	NM_015141.4	c.408C>T	p.Asp136Asp	synonymous_variant	4/8	ENST00000282541.10	NP_055956.1
GPD1L	XM_006713068.3	c.267C>T	p.Asp89Asp	synonymous_variant	3/7		XP_006713131.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GPD1L	ENST00000282541.10	c.408C>T	p.Asp136Asp	synonymous_variant	4/8	1	NM_015141.4	ENSP00000282541.6

Frequencies

GnomAD3 genomes AF: 0.171 AC: 25981 AN: 151994 Hom.: 2792 Cov.: 32

Gnomad AFR AF: 0.299

Gnomad AMI AF: 0.170

Gnomad AMR AF: 0.118

Gnomad ASJ AF: 0.120

Gnomad EAS AF: 0.00251

Gnomad SAS AF: 0.141

Gnomad FIN AF: 0.0957

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.135

Gnomad OTH AF: 0.162

GnomAD3 exomes AF: 0.123 AC: 30986 AN: 251324 Hom.: 2475 AF XY: 0.123 AC XY: 16774 AN XY: 135822

Gnomad AFR exome AF: 0.303

Gnomad AMR exome AF: 0.0710

Gnomad ASJ exome AF: 0.121

Gnomad EAS exome AF: 0.000761

Gnomad SAS exome AF: 0.139

Gnomad FIN exome AF: 0.0970

Gnomad NFE exome AF: 0.135

Gnomad OTH exome AF: 0.123

GnomAD4 exome AF: 0.133 AC: 194805 AN: 1461528 Hom.: 14351 Cov.: 33 AF XY: 0.133 AC XY: 96939 AN XY: 727092

Gnomad4 AFR exome AF: 0.307

Gnomad4 AMR exome AF: 0.0795

Gnomad4 ASJ exome AF: 0.121

Gnomad4 EAS exome AF: 0.000630

Gnomad4 SAS exome AF: 0.138

Gnomad4 FIN exome AF: 0.0955

Gnomad4 NFE exome AF: 0.137

Gnomad4 OTH exome AF: 0.134

GnomAD4 genome AF: 0.171 AC: 25996 AN: 152112 Hom.: 2795 Cov.: 32 AF XY: 0.167 AC XY: 12430 AN XY: 74378

Gnomad4 AFR AF: 0.299

Gnomad4 AMR AF: 0.118

Gnomad4 ASJ AF: 0.120

Gnomad4 EAS AF: 0.00251

Gnomad4 SAS AF: 0.141

Gnomad4 FIN AF: 0.0957

Gnomad4 NFE AF: 0.135

Gnomad4 OTH AF: 0.159

Alfa AF: 0.140 Hom.: 3242

Bravo AF: 0.177

Asia WGS AF: 0.0850 AC: 295 AN: 3478

EpiCase AF: 0.136

EpiControl AF: 0.137

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Brugada syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 19, 2015

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
CADD	Benign	12
DANN	Benign	0.61

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: rs9835387; hg19: chr3-32181761; COSMIC: COSV56990087;