rs4767939

Variant names:

• chr12-111769091-A-G
• rs4767939
• NM_000690.4:c.114+1995A>G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000690.4(ALDH2):​c.114+1995A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.273 in 152,064 control chromosomes in the GnomAD database, including 7,464 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 0.27 (7464 hom., cov: 32)
• Consequence: ALDH2 NM_000690.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.18

Genes affected

ALDH2 (HGNC:404): (aldehyde dehydrogenase 2 family member) This protein belongs to the aldehyde dehydrogenase family of proteins. Aldehyde dehydrogenase is the second enzyme of the major oxidative pathway of alcohol metabolism. Two major liver isoforms of aldehyde dehydrogenase, cytosolic and mitochondrial, can be distinguished by their electrophoretic mobilities, kinetic properties, and subcellular localizations. Most Caucasians have two major isozymes, while approximately 50% of East Asians have the cytosolic isozyme but not the mitochondrial isozyme. A remarkably higher frequency of acute alcohol intoxication among East Asians than among Caucasians could be related to the absence of a catalytically active form of the mitochondrial isozyme. The increased exposure to acetaldehyde in individuals with the catalytically inactive form may also confer greater susceptibility to many types of cancer. This gene encodes a mitochondrial isoform, which has a low Km for acetaldehydes, and is localized in mitochondrial matrix. Alternative splicing results in multiple transcript variants encoding distinct isoforms.[provided by RefSeq, Nov 2016]

ENSG00000257767 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.834 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH2	NM_000690.4	c.114+1995A>G		intron_variant	Intron 1 of 12	ENST00000261733.7	NP_000681.2
ALDH2	NM_001204889.2	c.114+1995A>G		intron_variant	Intron 1 of 11		NP_001191818.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH2	ENST00000261733.7	c.114+1995A>G		intron_variant	Intron 1 of 12	1	NM_000690.4	ENSP00000261733.2
ENSG00000257767	ENST00000546840.3	c.103-12827A>G		intron_variant	Intron 2 of 7	5		ENSP00000450353.4
ALDH2	ENST00000416293.7	c.114+1995A>G		intron_variant	Intron 1 of 11	2		ENSP00000403349.3
ALDH2	ENST00000548536.1	n.114+1995A>G		intron_variant	Intron 1 of 13	3		ENSP00000448179.1

Frequencies

GnomAD3 genomes AF: 0.273 AC: 41528 AN: 151946 Hom.: 7466 Cov.: 32

Gnomad AFR AF: 0.400

Gnomad AMI AF: 0.146

Gnomad AMR AF: 0.298

Gnomad ASJ AF: 0.0966

Gnomad EAS AF: 0.855

Gnomad SAS AF: 0.314

Gnomad FIN AF: 0.154

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.173

Gnomad OTH AF: 0.279

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.273 AC: 41568 AN: 152064 Hom.: 7464 Cov.: 32 AF XY: 0.277 AC XY: 20565 AN XY: 74332

Gnomad4 AFR AF: 0.400

Gnomad4 AMR AF: 0.298

Gnomad4 ASJ AF: 0.0966

Gnomad4 EAS AF: 0.855

Gnomad4 SAS AF: 0.314

Gnomad4 FIN AF: 0.154

Gnomad4 NFE AF: 0.173

Gnomad4 OTH AF: 0.277

Alfa AF: 0.196 Hom.: 4426

Bravo AF: 0.295

Asia WGS AF: 0.516 AC: 1792 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.25
DANN	Benign	0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs4767939; hg19: chr12-112206895;