chr4-99427779-A-G

Variant names:

• chr4-99427779-A-G
• rs370255803
• NM_000673.7:c.558T>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_000673.7(ADH7):​c.558T>C​(p.Thr186Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000828 in 1,534,318 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000083 (0 hom.)
• Consequence: ADH7 NM_000673.7 synonymous
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: -0.309
• Publications: 0 publications found

Genes affected

ADH7 (HGNC:256): (alcohol dehydrogenase 7 (class IV), mu or sigma polypeptide) This gene encodes class IV alcohol dehydrogenase 7 mu or sigma subunit, which is a member of the alcohol dehydrogenase family. Members of this family metabolize a wide variety of substrates, including ethanol, retinol, other aliphatic alcohols, hydroxysteroids, and lipid peroxidation products. The enzyme encoded by this gene is inefficient in ethanol oxidation, but is the most active as a retinol dehydrogenase; thus it may participate in the synthesis of retinoic acid, a hormone important for cellular differentiation. The expression of this gene is much more abundant in stomach than liver, thus differing from the other known gene family members. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP7: Synonymous conserved (PhyloP=-0.309 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000673.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADH7	NM_000673.7	MANE Select	c.558T>C	p.Thr186Thr	synonymous	Exon 5 of 9	NP_000664.3	A0A0C4DG85
	ADH7	NM_001166504.2		c.618T>C	p.Thr206Thr	synonymous	Exon 5 of 9	NP_001159976.1	P40394-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADH7	ENST00000437033.7	TSL:1 MANE Select	c.558T>C	p.Thr186Thr	synonymous	Exon 5 of 9	ENSP00000414254.2	A0A0C4DG85
	ADH7	ENST00000209665.8	TSL:1	c.594T>C	p.Thr198Thr	synonymous	Exon 5 of 9	ENSP00000209665.4	P40394-1
	ADH7	ENST00000476959.5	TSL:2	c.618T>C	p.Thr206Thr	synonymous	Exon 5 of 9	ENSP00000420269.1	P40394-2

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 151996 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000900 AC: 18 AN: 200080 AF XY: 0.0000748

Gnomad AFR exome AF: 0.0000650

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000832 AC: 115 AN: 1382322 Hom.: 0 Cov.: 32 AF XY: 0.0000884 AC XY: 60 AN XY: 679050

African (AFR) AF: 0.0000644 AC: 2 AN: 31040

American (AMR) AF: 0.00 AC: 0 AN: 33006

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21828

East Asian (EAS) AF: 0.00 AC: 0 AN: 38600

South Asian (SAS) AF: 0.00 AC: 0 AN: 71646

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51020

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5422

European-Non Finnish (NFE) AF: 0.000102 AC: 109 AN: 1072882

Other (OTH) AF: 0.0000703 AC: 4 AN: 56878

GnomAD4 genome AF: 0.0000789 AC: 12 AN: 151996 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74240

African (AFR) AF: 0.0000725 AC: 3 AN: 41388

American (AMR) AF: 0.00 AC: 0 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68002

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000304 Hom.: 0

Bravo AF: 0.0000907

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	ADH7-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.3
DANN	Benign	0.52
PhyloP100		-0.31
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs370255803; hg19: chr4-100348936;