12-6537943-T-C

Variant names:

• chr12-6537943-T-C
• rs1803621
• NM_002046.7:c.885T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_002046.7(GAPDH):​c.885T>C​(p.Phe295Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.243 in 1,607,910 control chromosomes in the GnomAD database, including 51,331 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.32 (8679 hom., cov: 33)
  • Exomes 𝑓: 0.23 (42652 hom.)
• Consequence: GAPDH NM_002046.7 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.439

Genes affected

GAPDH (HGNC:4141): (glyceraldehyde-3-phosphate dehydrogenase) This gene encodes a member of the glyceraldehyde-3-phosphate dehydrogenase protein family. The encoded protein has been identified as a moonlighting protein based on its ability to perform mechanistically distinct functions. The product of this gene catalyzes an important energy-yielding step in carbohydrate metabolism, the reversible oxidative phosphorylation of glyceraldehyde-3-phosphate in the presence of inorganic phosphate and nicotinamide adenine dinucleotide (NAD). The encoded protein has additionally been identified to have uracil DNA glycosylase activity in the nucleus. Also, this protein contains a peptide that has antimicrobial activity against E. coli, P. aeruginosa, and C. albicans. Studies of a similar protein in mouse have assigned a variety of additional functions including nitrosylation of nuclear proteins, the regulation of mRNA stability, and acting as a transferrin receptor on the cell surface of macrophage. Many pseudogenes similar to this locus are present in the human genome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2014]

ENSG00000269968 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP7: Synonymous conserved (PhyloP=-0.439 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.511 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAPDH	NM_002046.7	c.885T>C	p.Phe295Phe	synonymous_variant	Exon 8 of 9	ENST00000229239.10	NP_002037.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAPDH	ENST00000229239.10	c.885T>C	p.Phe295Phe	synonymous_variant	Exon 8 of 9	1	NM_002046.7	ENSP00000229239.5

Frequencies

GnomAD3 genomes AF: 0.316 AC: 47690 AN: 151088 Hom.: 8653 Cov.: 33

Gnomad AFR AF: 0.491

Gnomad AMI AF: 0.262

Gnomad AMR AF: 0.321

Gnomad ASJ AF: 0.176

Gnomad EAS AF: 0.528

Gnomad SAS AF: 0.281

Gnomad FIN AF: 0.276

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.210

Gnomad OTH AF: 0.268

GnomAD2 exomes AF: 0.278 AC: 68940 AN: 247878 AF XY: 0.268

Gnomad AFR exome AF: 0.500

Gnomad AMR exome AF: 0.314

Gnomad ASJ exome AF: 0.165

Gnomad EAS exome AF: 0.534

Gnomad FIN exome AF: 0.276

Gnomad NFE exome AF: 0.208

Gnomad OTH exome AF: 0.232

GnomAD4 exome AF: 0.235 AC: 342217 AN: 1456710 Hom.: 42652 Cov.: 35 AF XY: 0.233 AC XY: 169052 AN XY: 724042

African (AFR) AF: 0.494 AC: 16539 AN: 33450

American (AMR) AF: 0.318 AC: 13867 AN: 43602

Ashkenazi Jewish (ASJ) AF: 0.169 AC: 4423 AN: 26124

East Asian (EAS) AF: 0.523 AC: 20202 AN: 38644

South Asian (SAS) AF: 0.271 AC: 22766 AN: 84100

European-Finnish (FIN) AF: 0.271 AC: 14443 AN: 53352

Middle Eastern (MID) AF: 0.156 AC: 897 AN: 5752

European-Non Finnish (NFE) AF: 0.210 AC: 233860 AN: 1111562

Other (OTH) AF: 0.253 AC: 15220 AN: 60124

GnomAD4 genome AF: 0.316 AC: 47769 AN: 151200 Hom.: 8679 Cov.: 33 AF XY: 0.319 AC XY: 23554 AN XY: 73842

African (AFR) AF: 0.492 AC: 20415 AN: 41496

American (AMR) AF: 0.321 AC: 4708 AN: 14686

Ashkenazi Jewish (ASJ) AF: 0.176 AC: 611 AN: 3470

East Asian (EAS) AF: 0.528 AC: 2670 AN: 5056

South Asian (SAS) AF: 0.280 AC: 1292 AN: 4618

European-Finnish (FIN) AF: 0.276 AC: 2928 AN: 10600

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.210 AC: 14283 AN: 67972

Other (OTH) AF: 0.272 AC: 570 AN: 2096

Alfa AF: 0.229 Hom.: 1482

Bravo AF: 0.328

Asia WGS AF: 0.459 AC: 1592 AN: 3478

EpiCase AF: 0.195

EpiControl AF: 0.188

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	0.27
DANN	Benign	0.66
PhyloP100		-0.44
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Other links and lift over

dbSNP: rs1803621; hg19: chr12-6647109; COSMIC: COSV57520486; COSMIC: COSV57520486;