Genetic Variant GAPDHS:p.Asp377His (chr19-35544981-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_014364.5(GAPDHS):c.1129G>C(p.Asp377His) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,508 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D377N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

GAPDHS
NM_014364.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.33

Publications

0 publications found

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014364.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAPDHS	NM_014364.5	MANE Select	c.1129G>C	p.Asp377His	missense	Exon 10 of 11	NP_055179.1
	TMEM147-AS1	NR_038396.1		n.93+956C>G		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GAPDHS	ENST00000222286.9	TSL:1 MANE Select	c.1129G>C	p.Asp377His	missense	Exon 10 of 11	ENSP00000222286.3
TMEM147-AS1	ENST00000590717.2	TSL:1	n.527C>G		non_coding_transcript_exon	Exon 1 of 3
TMEM147-AS1	ENST00000589137.5	TSL:1	n.93+956C>G		intron	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461508

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727080

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33470

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111662

Other (OTH)

AF:

0.00

AC:

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.600

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

0.00085

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.51

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.97

M_CAP

Benign

0.079

MetaRNN

Uncertain

0.73

MetaSVM

Benign

-0.42

MutationAssessor

Pathogenic

3.5

PhyloP100

4.3

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-2.8

REVEL

Uncertain

0.32

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0020

Polyphen

0.85

Vest4

0.59

MutPred

0.48

Loss of sheet (P = 0.0011)

MVP

0.73

MPC

2.3

ClinPred

0.99

GERP RS

1.8

Varity_R

0.66

gMVP

0.68

Mutation Taster

=79/21

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over