rs1136666

Variant names:

• chr12-6534825-C-G
• rs1136666
• NM_002046.7:c.-8C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002046.7(GAPDH):​c.-8C>G variant causes a 5 prime UTR premature start codon gain 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_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.214
• Publications: 24 publications found

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

Our verdict: Benign. The variant received -20 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 VariationId is 1262368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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 rank	MANE	Protein	UniProt
GAPDH	NM_002046.7	c.-8C>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 9	ENST00000229239.10	NP_002037.2
GAPDH	NM_002046.7	c.-8C>G		5_prime_UTR_variant	Exon 2 of 9	ENST00000229239.10	NP_002037.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAPDH	ENST00000229239.10	c.-8C>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 9	1	NM_002046.7	ENSP00000229239.5
GAPDH	ENST00000229239.10	c.-8C>G		5_prime_UTR_variant	Exon 2 of 9	1	NM_002046.7	ENSP00000229239.5

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

GnomAD2 exomes AF: 0.237 AC: 59104 AN: 248998 AF XY: 0.232

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 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

African (AFR) AF: 0.284 AC: 9506 AN: 33422

American (AMR) AF: 0.233 AC: 10408 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.115 AC: 3004 AN: 26114

East Asian (EAS) AF: 0.192 AC: 7630 AN: 39652

South Asian (SAS) AF: 0.164 AC: 14120 AN: 86236

European-Finnish (FIN) AF: 0.264 AC: 14063 AN: 53182

Middle Eastern (MID) AF: 0.104 AC: 590 AN: 5674

European-Non Finnish (NFE) AF: 0.273 AC: 303063 AN: 1111058

Other (OTH) AF: 0.244 AC: 14700 AN: 60342

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

African (AFR) AF: 0.288 AC: 11936 AN: 41504

American (AMR) AF: 0.241 AC: 3691 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 387 AN: 3472

East Asian (EAS) AF: 0.220 AC: 1141 AN: 5180

South Asian (SAS) AF: 0.167 AC: 805 AN: 4834

European-Finnish (FIN) AF: 0.258 AC: 2738 AN: 10594

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.268 AC: 18187 AN: 67978

Other (OTH) AF: 0.221 AC: 466 AN: 2108

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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 22, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		0.21
PromoterAI		0.0079	Neutral
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Mutation Taster		=300/0	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

Other links and lift over

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