3-32158910-G-C

Variant names:

• chr3-32158910-G-C
• rs148361833
• NM_015141.4:c.653G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_015141.4(GPD1L):​c.653G>C​(p.Gly218Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G218S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GPD1L NM_015141.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.87
• Publications: 1 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.908

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.653G>C	p.Gly218Ala	missense	Exon 6 of 8	NP_055956.1	Q8N335

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPD1L	ENST00000282541.10	TSL:1 MANE Select	c.653G>C	p.Gly218Ala	missense	Exon 6 of 8	ENSP00000282541.6	Q8N335
	GPD1L	ENST00000902849.1		c.650G>C	p.Gly217Ala	missense	Exon 6 of 8	ENSP00000572908.1
	GPD1L	ENST00000951742.1		c.260G>C	p.Gly87Ala	missense	Exon 3 of 5	ENSP00000621801.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Brugada syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.083	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	0.47	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		9.9
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Pathogenic	0.81
Sift	Benign	0.031	D
Sift4G	Benign	0.068	T
Polyphen		1.0	D
Vest4		0.97
MVP		0.93
MPC		1.3
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.80
gMVP		0.93
Mutation Taster		=21/79	disease causing

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

Other links and lift over

dbSNP: rs148361833; hg19: chr3-32200402;