Genetic Variant GPD1L:p.Ser346Arg (chr3-32165892-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_015141.4(GPD1L):c.1038C>A(p.Ser346Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,435,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S346S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

GPD1L
NM_015141.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.60

Publications

0 publications found

Variant links:

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]

GPD1L Gene-Disease associations (from GenCC):

Brugada syndrome 2
Inheritance: AD, Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
Brugada syndrome 1
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

GPD1L links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.23810625).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015141.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPD1L	NM_015141.4	MANE Select	c.1038C>A	p.Ser346Arg	missense	Exon 8 of 8	NP_055956.1	Q8N335

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GPD1L	ENST00000282541.10	TSL:1 MANE Select	c.1038C>A	p.Ser346Arg	missense	Exon 8 of 8	ENSP00000282541.6	Q8N335
GPD1L	ENST00000902849.1		c.1035C>A	p.Ser345Arg	missense	Exon 8 of 8	ENSP00000572908.1
GPD1L	ENST00000902848.1		c.804C>A	p.Ser268Arg	missense	Exon 7 of 7	ENSP00000572907.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000139

AC:

AN:

1435834

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

715978

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33002

American (AMR)

AF:

0.00

AC:

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25984

East Asian (EAS)

AF:

0.00

AC:

AN:

39572

South Asian (SAS)

AF:

0.00

AC:

AN:

85782

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5718

European-Non Finnish (NFE)

AF:

0.00000184

AC:

AN:

1088158

Other (OTH)

AF:

0.00

AC:

AN:

59504

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.097

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.15

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.49

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.65

M_CAP

Benign

0.039

MetaRNN

Benign

0.24

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.4

PhyloP100

1.6

PrimateAI

Benign

0.48

PROVEAN

Benign

-1.4

REVEL

Benign

0.044

Sift

Uncertain

0.018

Sift4G

Benign

0.18

Polyphen

0.054

Vest4

0.15

MutPred

0.29

Loss of glycosylation at S346 (P = 0.0362)

MVP

0.69

MPC

0.45

ClinPred

0.66

GERP RS

0.98

Varity_R

0.23

gMVP

0.40

Mutation Taster

=55/45

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over