rs1136666

chr12-6534825-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002046.7(GAPDH):c.-8C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.258 in 1,612,562 control chromosomes in the GnomAD database, including 55,507 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.26 (5213 hom., cov: 33)
  • Exomes 𝑓: 0.26 (50294 hom.)
• Consequence: GAPDH NM_002046.7 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.214

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 12-6534825-C-G is Benign according to our data. Variant chr12-6534825-C-G is described in ClinVar as [Benign]. Clinvar id is 1262368.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.283 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAPDH	NM_002046.7	c.-8C>G		5_prime_UTR_variant	2/9	ENST00000229239.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAPDH	ENST00000229239.10	c.-8C>G		5_prime_UTR_variant	2/9	1	NM_002046.7	P1

Frequencies

GnomAD3 genomes AF: 0.260 AC: 39529 AN: 152054 Hom.: 5201 Cov.: 33

Gnomad AFR AF: 0.287

Gnomad AMI AF: 0.203

Gnomad AMR AF: 0.241

Gnomad ASJ AF: 0.111

Gnomad EAS AF: 0.219

Gnomad SAS AF: 0.167

Gnomad FIN AF: 0.258

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.268

Gnomad OTH AF: 0.223

GnomAD3 exomes AF: 0.237 AC: 59104 AN: 248998 Hom.: 7396 AF XY: 0.232 AC XY: 31306 AN XY: 135000

Gnomad AFR exome AF: 0.287

Gnomad AMR exome AF: 0.229

Gnomad ASJ exome AF: 0.114

Gnomad EAS exome AF: 0.219

Gnomad SAS exome AF: 0.171

Gnomad FIN exome AF: 0.260

Gnomad NFE exome AF: 0.261

Gnomad OTH exome AF: 0.224

GnomAD4 exome AF: 0.258 AC: 377084 AN: 1460390 Hom.: 50294 Cov.: 34 AF XY: 0.254 AC XY: 184474 AN XY: 726586

Gnomad4 AFR exome AF: 0.284

Gnomad4 AMR exome AF: 0.233

Gnomad4 ASJ exome AF: 0.115

Gnomad4 EAS exome AF: 0.192

Gnomad4 SAS exome AF: 0.164

Gnomad4 FIN exome AF: 0.264

Gnomad4 NFE exome AF: 0.273

Gnomad4 OTH exome AF: 0.244

GnomAD4 genome AF: 0.260 AC: 39565 AN: 152172 Hom.: 5213 Cov.: 33 AF XY: 0.255 AC XY: 19006 AN XY: 74418

Gnomad4 AFR AF: 0.288

Gnomad4 AMR AF: 0.241

Gnomad4 ASJ AF: 0.111

Gnomad4 EAS AF: 0.220

Gnomad4 SAS AF: 0.167

Gnomad4 FIN AF: 0.258

Gnomad4 NFE AF: 0.268

Gnomad4 OTH AF: 0.221

Alfa AF: 0.249 Hom.: 1660

Bravo AF: 0.262

Asia WGS AF: 0.214 AC: 744 AN: 3478

EpiCase AF: 0.240

EpiControl AF: 0.233

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 22, 2019

This variant is associated with the following publications: (PMID: 29886133) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
Cadd	Benign	14
Dann	Benign	0.69
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1

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

LitVar

Other links and lift over

dbSNP: rs1136666; hg19: chr12-6643991; COSMIC: COSV57520988; COSMIC: COSV57520988;