11-64935405-G-T

Variant names:

• chr11-64935405-G-T
• NM_130769.4:c.56C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_130769.4(GPHA2):​c.56C>A​(p.Thr19Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GPHA2 NM_130769.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.61

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12637019).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPHA2	NM_130769.4	c.56C>A	p.Thr19Asn	missense_variant	Exon 2 of 4	ENST00000279168.7	NP_570125.1
GPHA2	XM_011544776.3	c.56C>A	p.Thr19Asn	missense_variant	Exon 2 of 4		XP_011543078.1
GPHA2	XM_047426491.1	c.56C>A	p.Thr19Asn	missense_variant	Exon 2 of 4		XP_047282447.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPHA2	ENST00000279168.7	c.56C>A	p.Thr19Asn	missense_variant	Exon 2 of 4	1	NM_130769.4	ENSP00000279168.2
GPHA2	ENST00000533257.1	c.56C>A	p.Thr19Asn	missense_variant	Exon 1 of 3	2		ENSP00000432918.1
GPHA2	ENST00000532246.1	c.56C>A	p.Thr19Asn	missense_variant	Exon 2 of 3	3		ENSP00000431352.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.56C>A (p.T19N) alteration is located in exon 2 (coding exon 1) of the GPHA2 gene. This alteration results from a C to A substitution at nucleotide position 56, causing the threonine (T) at amino acid position 19 to be replaced by an asparagine (N). 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	0.12
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	7.8
DANN	Uncertain	0.98
DEOGEN2	Benign	0.051	T;T;.
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.63	.;T;T
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.1	M;M;.
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.95	N;N;N
REVEL	Benign	0.047
Sift	Benign	0.037	D;D;D
Sift4G	Benign	0.48	T;T;T
Polyphen		0.40	B;B;.
Vest4		0.35
MutPred		0.30		Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);
MVP		0.38
MPC		0.31
ClinPred		0.49	T
GERP RS		3.2
Varity_R		0.068
gMVP		0.38

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-64702877;