12-6535615-T-C

Variant names:

• chr12-6535615-T-C
• rs1060619
• NM_002046.7:c.29+754T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002046.7(GAPDH):​c.29+754T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.276 in 246,346 control chromosomes in the GnomAD database, including 10,945 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 0.31 (8385 hom., cov: 32)
  • Exomes 𝑓: 0.23 (2560 hom.)
• Consequence: GAPDH NM_002046.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.180
• Publications: 15 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.484 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002046.7. 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
	GAPDH	NM_002046.7	MANE Select	c.29+754T>C		intron	N/A	NP_002037.2
	GAPDH	NM_001289745.3		c.29+754T>C		intron	N/A	NP_001276674.1
	GAPDH	NM_001289746.2		c.29+754T>C		intron	N/A	NP_001276675.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAPDH	ENST00000229239.10	TSL:1 MANE Select	c.29+754T>C		intron	N/A	ENSP00000229239.5
	GAPDH	ENST00000396859.5	TSL:1	c.29+754T>C		intron	N/A	ENSP00000380068.1
	GAPDH	ENST00000396861.5	TSL:5	c.29+754T>C		intron	N/A	ENSP00000380070.1

Frequencies

GnomAD3 genomes AF: 0.306 AC: 46401 AN: 151834 Hom.: 8357 Cov.: 32

Gnomad AFR AF: 0.489

Gnomad AMI AF: 0.236

Gnomad AMR AF: 0.282

Gnomad ASJ AF: 0.175

Gnomad EAS AF: 0.489

Gnomad SAS AF: 0.262

Gnomad FIN AF: 0.273

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.203

Gnomad OTH AF: 0.260

GnomAD4 exome AF: 0.227 AC: 21448 AN: 94394 Hom.: 2560 AF XY: 0.226 AC XY: 10264 AN XY: 45336

African (AFR) AF: 0.504 AC: 844 AN: 1676

American (AMR) AF: 0.433 AC: 39 AN: 90

Ashkenazi Jewish (ASJ) AF: 0.166 AC: 93 AN: 560

East Asian (EAS) AF: 0.506 AC: 179 AN: 354

South Asian (SAS) AF: 0.276 AC: 537 AN: 1948

European-Finnish (FIN) AF: 0.184 AC: 7 AN: 38

Middle Eastern (MID) AF: 0.129 AC: 25 AN: 194

European-Non Finnish (NFE) AF: 0.219 AC: 18899 AN: 86474

Other (OTH) AF: 0.270 AC: 825 AN: 3060

GnomAD4 genome AF: 0.306 AC: 46477 AN: 151952 Hom.: 8385 Cov.: 32 AF XY: 0.308 AC XY: 22840 AN XY: 74262

African (AFR) AF: 0.489 AC: 20261 AN: 41402

American (AMR) AF: 0.282 AC: 4300 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.175 AC: 608 AN: 3470

East Asian (EAS) AF: 0.489 AC: 2526 AN: 5164

South Asian (SAS) AF: 0.260 AC: 1253 AN: 4818

European-Finnish (FIN) AF: 0.273 AC: 2890 AN: 10570

Middle Eastern (MID) AF: 0.173 AC: 51 AN: 294

European-Non Finnish (NFE) AF: 0.203 AC: 13819 AN: 67960

Other (OTH) AF: 0.264 AC: 554 AN: 2102

Alfa AF: 0.242 Hom.: 11075

Bravo AF: 0.316

Asia WGS AF: 0.425 AC: 1476 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	8.7
DANN	Benign	0.72
PhyloP100		-0.18
PromoterAI		0.048	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1060619; hg19: chr12-6644781;