Variant chr19-35542518-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_014364.5(GAPDHS):c.569T>C(p.Val190Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,714 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

GAPDHS
NM_014364.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.69

Variant links:

Genes affected

GAPDHS (HGNC:24864): (glyceraldehyde-3-phosphate dehydrogenase, spermatogenic) This gene encodes a protein belonging to the glyceraldehyde-3-phosphate dehydrogenase family of enzymes that play an important role in carbohydrate metabolism. Like its somatic cell counterpart, this sperm-specific enzyme functions in a nicotinamide adenine dinucleotide-dependent manner to remove hydrogen and add phosphate to glyceraldehyde 3-phosphate to form 1,3-diphosphoglycerate. During spermiogenesis, this enzyme may play an important role in regulating the switch between different energy-producing pathways, and it is required for sperm motility and male fertility. [provided by RefSeq, Jul 2008]

GAPDHS links:

TMEM147-AS1 (HGNC:51273): (TMEM147 antisense RNA 1)

TMEM147-AS1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.971

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAPDHS	NM_014364.5 link	c.569T>C	p.Val190Ala	missense_variant	6/11	ENST00000222286.9	NP_055179.1	O14556A0A0K0K1K1
TMEM147-AS1	NR_038396.1 link	n.456+393A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAPDHS	ENST00000222286.9 link	c.569T>C	p.Val190Ala	missense_variant	6/11	1	NM_014364.5	ENSP00000222286.3		O14556

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251218

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135776

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461714

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727152

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 01, 2024

The c.569T>C (p.V190A) alteration is located in exon 6 (coding exon 6) of the GAPDHS gene. This alteration results from a T to C substitution at nucleotide position 569, causing the valine (V) at amino acid position 190 to be replaced by an alanine (A). 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

0.63

BayesDel_addAF

Uncertain

0.044

BayesDel_noAF

Uncertain

0.090

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.46

T;T

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.80

T;T

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Uncertain

0.010

MutationAssessor

Pathogenic

3.9

H;.

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-3.3

D;.

REVEL

Uncertain

0.59

Sift

Uncertain

0.0040

D;.

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;.

Vest4

0.95

MutPred

0.90

Gain of disorder (P = 0.036);.;

MVP

0.75

MPC

0.68

ClinPred

0.84

GERP RS

5.0

Varity_R

0.83

gMVP

0.80

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