4-99072440-T-C

Position:

• chr4-99072440-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000671.4(ADH5):​c.1102A>G​(p.Ile368Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ADH5 NM_000671.4 missense, splice_region
• Scores: Splicing: ADA: 0.3104
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.51

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13419989).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADH5	NM_000671.4	c.1102A>G	p.Ile368Val	missense_variant, splice_region_variant	9/9	ENST00000296412.14	NP_000662.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADH5	ENST00000296412.14	c.1102A>G	p.Ile368Val	missense_variant, splice_region_variant	9/9	1	NM_000671.4	ENSP00000296412.8
ADH5	ENST00000626055.2	c.*789A>G		splice_region_variant	8/8	5		ENSP00000487496.1
ADH5	ENST00000626055.2	c.*789A>G		3_prime_UTR_variant	8/8	5		ENSP00000487496.1
ADH5	ENST00000512621.5	n.1221A>G		non_coding_transcript_exon_variant	7/7	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 15, 2024

The c.1102A>G (p.I368V) alteration is located in exon 9 (coding exon 9) of the ADH5 gene. This alteration results from a A to G substitution at nucleotide position 1102, causing the isoleucine (I) at amino acid position 368 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.051
Eigen_PC	Benign	0.061
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.1	M
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.77	N
REVEL	Benign	0.12
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.037	D
Polyphen		0.0040	B
Vest4		0.082
MutPred		0.48		Loss of methylation at K373 (P = 0.111);
MVP		0.46
MPC		0.35
ClinPred		0.65	D
GERP RS		4.0
Varity_R		0.46
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.31
dbscSNV1_RF	Benign	0.58
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-99993591;