chr3-32106722-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_015141.4(GPD1L):​c.11C>T​(p.Ala4Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000307 in 1,563,388 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A4E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

GPD1L
NM_015141.4 missense

Scores

2
1
16

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 1.74
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.20171258).
BP6
Variant 3-32106722-C-T is Benign according to our data. Variant chr3-32106722-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 666385.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}. Variant chr3-32106722-C-T is described in Lovd as [Likely_benign].
BS2
High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GPD1LNM_015141.4 linkc.11C>T p.Ala4Val missense_variant Exon 1 of 8 ENST00000282541.10 NP_055956.1 Q8N335
GPD1LXM_006713068.3 linkc.11C>T p.Ala4Val missense_variant Exon 1 of 7 XP_006713131.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GPD1LENST00000282541.10 linkc.11C>T p.Ala4Val missense_variant Exon 1 of 8 1 NM_015141.4 ENSP00000282541.6 Q8N335

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152068
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000736
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.0000305
AC:
43
AN:
1411212
Hom.:
0
Cov.:
30
AF XY:
0.0000356
AC XY:
25
AN XY:
701758
show subpopulations
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:
0.0000123
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000377
Gnomad4 OTH exome
AF:
0.0000173
GnomAD4 genome
AF:
0.0000329
AC:
5
AN:
152176
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74416
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000736
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000565
Hom.:
0
Bravo
AF:
0.0000151
ExAC
AF:
0.0000333
AC:
4

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Brugada syndrome Uncertain:1
Nov 08, 2021
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 4 of the GPD1L protein (p.Ala4Val). 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 variant has not been reported in the literature in individuals affected with GPD1L-related conditions. ClinVar contains an entry for this variant (Variation ID: 666385). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. -

Cardiovascular phenotype Benign:1
Feb 07, 2025
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as likely 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
AlphaMissense
Benign
0.17
BayesDel_addAF
Benign
-0.10
T
BayesDel_noAF
Benign
-0.39
CADD
Uncertain
24
DANN
Uncertain
0.98
DEOGEN2
Benign
0.17
T;.
Eigen
Benign
-0.14
Eigen_PC
Benign
0.036
FATHMM_MKL
Benign
0.56
D
LIST_S2
Benign
0.78
T;T
M_CAP
Pathogenic
0.72
D
MetaRNN
Benign
0.20
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.8
L;.
PrimateAI
Pathogenic
0.81
D
PROVEAN
Benign
-1.4
N;N
REVEL
Benign
0.046
Sift
Benign
0.11
T;T
Sift4G
Benign
0.11
T;D
Polyphen
0.0
B;.
Vest4
0.13
MVP
0.69
MPC
0.39
ClinPred
0.64
D
GERP RS
4.4
Varity_R
0.21
gMVP
0.37

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs201152084; hg19: chr3-32148214; API