rs778587185

Variant names:

• chr4-99314075-G-A
• rs778587185
• NM_000668.6:c.574C>T

Your query was ambiguous. Multiple possible variants found:

• chr4-99314075-G-A
• chr4-99314075-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000668.6(ADH1B):​c.574C>T​(p.Pro192Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,684 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ADH1B NM_000668.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.73
• Publications: 1 publications found

Genes affected

ADH1B (HGNC:250): (alcohol dehydrogenase 1B (class I), beta polypeptide) The protein encoded by this gene is a member of the alcohol dehydrogenase family. Members of this enzyme family metabolize a wide variety of substrates, including ethanol, retinol, other aliphatic alcohols, hydroxysteroids, and lipid peroxidation products. This encoded protein, consisting of several homo- and heterodimers of alpha, beta, and gamma subunits, exhibits high activity for ethanol oxidation and plays a major role in ethanol catabolism. Three genes encoding alpha, beta and gamma subunits are tandemly organized in a genomic segment as a gene cluster. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2013]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39246774).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000668.6. 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
	ADH1B	NM_000668.6	MANE Select	c.574C>T	p.Pro192Ser	missense	Exon 6 of 9	NP_000659.2
	ADH1B	NM_001286650.2		c.454C>T	p.Pro152Ser	missense	Exon 7 of 10	NP_001273579.1	D6RHZ6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADH1B	ENST00000305046.13	TSL:1 MANE Select	c.574C>T	p.Pro192Ser	missense	Exon 6 of 9	ENSP00000306606.8	P00325-1
	ADH1B	ENST00000625860.2	TSL:1	c.454C>T	p.Pro152Ser	missense	Exon 6 of 9	ENSP00000486614.1	P00325-2
	ADH1B	ENST00000881106.1		c.574C>T	p.Pro192Ser	missense	Exon 6 of 9	ENSP00000551165.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 249924 AF XY: 0.00000741

Gnomad AFR exome AF: 0.00

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: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460684 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 726486

African (AFR) AF: 0.00 AC: 0 AN: 33398

American (AMR) AF: 0.00 AC: 0 AN: 44566

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26058

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86072

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111400

Other (OTH) AF: 0.00 AC: 0 AN: 60344

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.085	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.0081	T
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-0.85	T
PhyloP100		2.7
PrimateAI	Benign	0.29	T
PROVEAN	Pathogenic	-6.8	D
REVEL	Benign	0.20
Sift	Benign	0.034	D
Sift4G	Uncertain	0.047	D
Vest4		0.14
MutPred		0.51		Gain of catalytic residue at P192 (P = 0.0233)
MVP		0.39
MPC		0.21
ClinPred		0.42	T
GERP RS		2.9
gMVP		0.37
Mutation Taster		=63/37	polymorphism

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: rs778587185; hg19: chr4-100235232;