Genetic Variant GPHA2:p.Arg44Cys (chr11-64935149-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_130769.4(GPHA2):c.130C>T(p.Arg44Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000719 in 1,613,770 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00041 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000037 ( 1 hom. )

Consequence

GPHA2
NM_130769.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.44

Variant links:

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]

GPHA2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1771065).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPHA2	NM_130769.4 link	c.130C>T	p.Arg44Cys	missense_variant	Exon 3 of 4	ENST00000279168.7	NP_570125.1	Q96T91A0A024R579
GPHA2	XM_011544776.3 link	c.130C>T	p.Arg44Cys	missense_variant	Exon 3 of 4		XP_011543078.1	Q96T91A0A024R579
GPHA2	XM_047426491.1 link	c.130C>T	p.Arg44Cys	missense_variant	Exon 3 of 4		XP_047282447.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GPHA2	ENST00000279168.7 link	c.130C>T	p.Arg44Cys	missense_variant	Exon 3 of 4	1	NM_130769.4	ENSP00000279168.2	Q96T91
GPHA2	ENST00000533257.1 link	c.130C>T	p.Arg44Cys	missense_variant	Exon 2 of 3	2		ENSP00000432918.1	Q96T91
GPHA2	ENST00000532246.1 link	c.130C>T	p.Arg44Cys	missense_variant	Exon 3 of 3	3		ENSP00000431352.1	E9PLQ0

Frequencies

GnomAD3 genomes

AF:

0.000408

AC:

AN:

151988

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00406

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000116

AC:

AN:

249066

Hom.:

AF XY:

0.0000890

AC XY:

AN XY:

134802

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000667

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000447

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000369

AC:

AN:

1461664

Hom.:

Cov.:

AF XY:

0.0000344

AC XY:

AN XY:

727126

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000738

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.000132

GnomAD4 genome

AF:

0.000408

AC:

AN:

152106

Hom.:

Cov.:

AF XY:

0.000538

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00406

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000554

Hom.:

Bravo

AF:

0.000529

ExAC

AF:

0.0000494

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 29, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.130C>T (p.R44C) alteration is located in exon 3 (coding exon 2) of the GPHA2 gene. This alteration results from a C to T substitution at nucleotide position 130, causing the arginine (R) at amino acid position 44 to be replaced by a cysteine (C). 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

Benign

0.20

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.19

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.070

T;T;.

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.91

.;D;D

M_CAP

Benign

0.035

MetaRNN

Benign

0.18

T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Uncertain

2.3

M;M;.

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.4

N;N;D

REVEL

Benign

0.19

Sift

Uncertain

0.0040

D;D;D

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

0.99

D;D;.

Vest4

0.69

MutPred

0.35

Loss of disorder (P = 0.0153);Loss of disorder (P = 0.0153);Loss of disorder (P = 0.0153);

MVP

0.41

MPC

0.98

ClinPred

0.17

GERP RS

4.2

Varity_R

0.17

gMVP

0.64

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over