chr19-35542556-G-C

Variant names:

• chr19-35542556-G-C
• rs757245260
• NM_014364.5:c.607G>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_014364.5(GAPDHS):​c.607G>C​(p.Val203Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,590 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GAPDHS NM_014364.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.68

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]

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

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.931

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAPDHS	NM_014364.5	c.607G>C	p.Val203Leu	missense_variant	Exon 6 of 11	ENST00000222286.9	NP_055179.1
TMEM147-AS1	NR_038396.1	n.456+355C>G		intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAPDHS	ENST00000222286.9	c.607G>C	p.Val203Leu	missense_variant	Exon 6 of 11	1	NM_014364.5	ENSP00000222286.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251388 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135876

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461590 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727146

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	T;T
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.078	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Pathogenic	3.9	H;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-2.4	N;.
REVEL	Uncertain	0.52
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.018	D;D
Polyphen		1.0	D;.
Vest4		0.80
MutPred		0.81		Loss of catalytic residue at V203 (P = 0.1412);.;
MVP		0.82
MPC		0.62
ClinPred		0.99	D
GERP RS		3.9
Varity_R		0.86
gMVP		0.75

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

Other links and lift over

dbSNP: rs757245260; hg19: chr19-36033458;