chr19-35536819-G-A

Variant names:

• chr19-35536819-G-A
• rs111439720
• NM_014364.5:c.74G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_014364.5(GAPDHS):​c.74G>A​(p.Arg25Lys) 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. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: GAPDHS NM_014364.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.72

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33157867).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAPDHS	NM_014364.5	c.74G>A	p.Arg25Lys	missense_variant	Exon 2 of 11	ENST00000222286.9	NP_055179.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAPDHS	ENST00000222286.9	c.74G>A	p.Arg25Lys	missense_variant	Exon 2 of 11	1	NM_014364.5	ENSP00000222286.3
GAPDHS	ENST00000585510	c.-131G>A		5_prime_UTR_variant	Exon 1 of 6	3		ENSP00000467255.1
GAPDHS	ENST00000586334.1	n.68-1488G>A		intron_variant	Intron 1 of 5	2		ENSP00000466432.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.090	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.20	T
Eigen	Benign	0.15
Eigen_PC	Benign	0.14
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.29	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.22	N
REVEL	Benign	0.15
Sift	Benign	0.034	D
Sift4G	Uncertain	0.019	D
Polyphen		0.96	P
Vest4		0.30
MutPred		0.19		Gain of ubiquitination at R25 (P = 0.0045);
MVP		0.57
MPC		0.56
ClinPred		0.84	D
GERP RS		4.3
Varity_R		0.18
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs111439720; hg19: chr19-36027721;