chr4-99075057-C-A

Variant names:

• chr4-99075057-C-A
• rs368604169
• NM_000671.4:c.826-8G>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_000671.4(ADH5):​c.826-8G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000496 in 1,594,518 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00052 (1 hom.)
• Consequence: ADH5 NM_000671.4 splice_region, intron
• Scores: Splicing: ADA: 0.0001881
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.504
• Publications: 1 publications found

Genes affected

ADH5 (HGNC:253): (alcohol dehydrogenase 5 (class III), chi polypeptide) This gene encodes 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 encoded protein forms a homodimer. It has virtually no activity for ethanol oxidation, but exhibits high activity for oxidation of long-chain primary alcohols and for oxidation of S-hydroxymethyl-glutathione, a spontaneous adduct between formaldehyde and glutathione. This enzyme is an important component of cellular metabolism for the elimination of formaldehyde, a potent irritant and sensitizing agent that causes lacrymation, rhinitis, pharyngitis, and contact dermatitis. The human genome contains several non-transcribed pseudogenes related to this gene. [provided by RefSeq, Oct 2008]

ADH5 Gene-Disease associations (from GenCC):

• AMED syndrome, digenic

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 4-99075057-C-A is Benign according to our data. Variant chr4-99075057-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2654962.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000671.4. 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
	ADH5	NM_000671.4	MANE Select	c.826-8G>T		splice_region intron	N/A	NP_000662.3	P11766

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADH5	ENST00000296412.14	TSL:1 MANE Select	c.826-8G>T		splice_region intron	N/A	ENSP00000296412.8	P11766
	ADH5	ENST00000885760.1		c.890G>T	p.Cys297Phe	missense	Exon 7 of 9	ENSP00000555819.1
	ADH5	ENST00000929296.1		c.629G>T	p.Cys210Phe	missense	Exon 6 of 8	ENSP00000599355.1

Frequencies

GnomAD3 genomes AF: 0.000289 AC: 44 AN: 152100 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.000529

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000181 AC: 43 AN: 237694 AF XY: 0.000202

Gnomad AFR exome AF: 0.000132

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000468

Gnomad NFE exome AF: 0.000358

Gnomad OTH exome AF: 0.000175

GnomAD4 exome AF: 0.000518 AC: 747 AN: 1442418 Hom.: 1 Cov.: 30 AF XY: 0.000543 AC XY: 389 AN XY: 716904

African (AFR) AF: 0.000122 AC: 4 AN: 32916

American (AMR) AF: 0.00 AC: 0 AN: 42558

Ashkenazi Jewish (ASJ) AF: 0.0000392 AC: 1 AN: 25484

East Asian (EAS) AF: 0.00 AC: 0 AN: 39136

South Asian (SAS) AF: 0.00 AC: 0 AN: 83238

European-Finnish (FIN) AF: 0.0000378 AC: 2 AN: 52876

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5666

European-Non Finnish (NFE) AF: 0.000641 AC: 706 AN: 1101006

Other (OTH) AF: 0.000571 AC: 34 AN: 59538

GnomAD4 genome AF: 0.000289 AC: 44 AN: 152100 Hom.: 0 Cov.: 33 AF XY: 0.000242 AC XY: 18 AN XY: 74286

African (AFR) AF: 0.000121 AC: 5 AN: 41400

American (AMR) AF: 0.000131 AC: 2 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

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

European-Non Finnish (NFE) AF: 0.000529 AC: 36 AN: 68018

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.000409 Hom.: 0

Bravo AF: 0.000253

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	4.2
DANN	Benign	0.65
PhyloP100		-0.50
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00019
dbscSNV1_RF	Benign	0.026
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: rs368604169; hg19: chr4-99996208;