rs72552293

Variant names:

• chr3-32140231-A-G
• rs72552293
• NM_015141.4:c.370A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_015141.4(GPD1L):​c.370A>G​(p.Ile124Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00175 in 1,614,054 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict 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. I124M) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0027 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (9 hom.)
• Consequence: GPD1L NM_015141.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:15
• Conservation: PhyloP100: 3.07
• Publications: 23 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008370727).
• BP6: Variant 3-32140231-A-G is Benign according to our data. Variant chr3-32140231-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 788.
• BS2: High AC in GnomAd4 at 417 AD,Unknown gene.

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.370A>G	p.Ile124Val	missense	Exon 4 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.370A>G	p.Ile124Val	missense	Exon 4 of 8	ENSP00000282541.6	Q8N335
	GPD1L	ENST00000902849.1		c.367A>G	p.Ile123Val	missense	Exon 4 of 8	ENSP00000572908.1
	GPD1L	ENST00000902848.1		c.370A>G	p.Ile124Val	missense	Exon 4 of 7	ENSP00000572907.1

Frequencies

GnomAD3 genomes AF: 0.00274 AC: 417 AN: 152138 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0198

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00284

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00251 AC: 630 AN: 251360 AF XY: 0.00244

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0167

Gnomad NFE exome AF: 0.00209

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00165 AC: 2412 AN: 1461798 Hom.: 9 Cov.: 32 AF XY: 0.00168 AC XY: 1219 AN XY: 727210

African (AFR) AF: 0.0000299 AC: 1 AN: 33470

American (AMR) AF: 0.000179 AC: 8 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000536 AC: 14 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86256

European-Finnish (FIN) AF: 0.0138 AC: 738 AN: 53416

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5754

European-Non Finnish (NFE) AF: 0.00139 AC: 1547 AN: 1111952

Other (OTH) AF: 0.00154 AC: 93 AN: 60396

GnomAD4 genome AF: 0.00274 AC: 417 AN: 152256 Hom.: 4 Cov.: 32 AF XY: 0.00341 AC XY: 254 AN XY: 74448

African (AFR) AF: 0.0000722 AC: 3 AN: 41566

American (AMR) AF: 0.000262 AC: 4 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.0198 AC: 210 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00284 AC: 193 AN: 68002

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00217 Hom.: 0

Bravo AF: 0.000907

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.00205 AC: 249

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00180

EpiControl AF: 0.00166

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	5	not provided (6)
1	1	2	Brugada syndrome 2 (4)
-	-	2	not specified (2)
-	-	1	Brugada syndrome (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	GPD1L-related disorder (1)
-	-	1	Hypertrophic cardiomyopathy (1)
-	-	1	Long QT syndrome;C0949658:Primary familial hypertrophic cardiomyopathy (1)
-	-	1	SUDDEN INFANT DEATH SYNDROME (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	16
DANN	Benign	0.53
DEOGEN2	Benign	0.059	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0084	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.080	N
PhyloP100		3.1
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.42	N
REVEL	Benign	0.29
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.15
MVP		0.14
MPC		0.33
ClinPred		0.015	T
GERP RS		3.9
Varity_R		0.16
gMVP		0.43
Mutation Taster		=74/26	polymorphism

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: rs72552293; hg19: chr3-32181723; COSMIC: COSV56990934;