11-64934789-C-A

Variant names:

• chr11-64934789-C-A
• rs573463788
• NM_130769.4:c.374G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_130769.4(GPHA2):​c.374G>T​(p.Arg125Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: GPHA2 NM_130769.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.90

Genes affected

GPHA2 (HGNC:18054): (glycoprotein hormone subunit alpha 2) GPHA2 is a cystine knot-forming polypeptide and a subunit of the dimeric glycoprotein hormone family (Hsu et al., 2002 [PubMed 12089349]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPHA2	NM_130769.4	c.374G>T	p.Arg125Leu	missense_variant	Exon 4 of 4	ENST00000279168.7	NP_570125.1
GPHA2	XM_011544776.3	c.374G>T	p.Arg125Leu	missense_variant	Exon 4 of 4		XP_011543078.1
GPHA2	XM_047426491.1	c.374G>T	p.Arg125Leu	missense_variant	Exon 4 of 4		XP_047282447.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPHA2	ENST00000279168.7	c.374G>T	p.Arg125Leu	missense_variant	Exon 4 of 4	1	NM_130769.4	ENSP00000279168.2
GPHA2	ENST00000533257.1	c.374G>T	p.Arg125Leu	missense_variant	Exon 3 of 3	2		ENSP00000432918.1
GPHA2	ENST00000532246.1	c.*133G>T		downstream_gene_variant		3		ENSP00000431352.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.374G>T (p.R125L) alteration is located in exon 4 (coding exon 3) of the GPHA2 gene. This alteration results from a G to T substitution at nucleotide position 374, causing the arginine (R) at amino acid position 125 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T;T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.88	.;D
M_CAP	Benign	0.025	D
MetaRNN	Uncertain	0.49	T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.6	M;M
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.9	D;D
REVEL	Benign	0.21
Sift	Uncertain	0.0080	D;D
Sift4G	Uncertain	0.012	D;D
Polyphen		1.0	D;D
Vest4		0.46
MutPred		0.45		Loss of MoRF binding (P = 0.0031);Loss of MoRF binding (P = 0.0031);
MVP		0.37
MPC		1.0
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.48
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs573463788; hg19: chr11-64702261;