NM_000671.4:c.962-7C>A

Variant names:

• chr4-99072718-G-T
• rs17595424
• NM_000671.4:c.962-7C>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_000671.4(ADH5):​c.962-7C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0907 in 1,597,514 control chromosomes in the GnomAD database, including 7,401 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.084 (574 hom., cov: 33)
  • Exomes 𝑓: 0.091 (6827 hom.)
• Consequence: ADH5 NM_000671.4 splice_region, intron
• Scores: Splicing: ADA: 0.0008288
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.333
• Publications: 14 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0983 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADH5	NM_000671.4	c.962-7C>A		splice_region_variant, intron_variant	Intron 7 of 8	ENST00000296412.14	NP_000662.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADH5	ENST00000296412.14	c.962-7C>A		splice_region_variant, intron_variant	Intron 7 of 8	1	NM_000671.4	ENSP00000296412.8
ADH5	ENST00000626055.2	c.*649-7C>A		splice_region_variant, intron_variant	Intron 6 of 7	5		ENSP00000487496.1
ADH5	ENST00000512621.5	n.950-7C>A		splice_region_variant, intron_variant	Intron 6 of 6	2

Frequencies

GnomAD3 genomes AF: 0.0842 AC: 12796 AN: 152060 Hom.: 574 Cov.: 33

Gnomad AFR AF: 0.0829

Gnomad AMI AF: 0.0526

Gnomad AMR AF: 0.0858

Gnomad ASJ AF: 0.0862

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0346

Gnomad FIN AF: 0.0447

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.100

Gnomad OTH AF: 0.0998

GnomAD2 exomes AF: 0.0745 AC: 17515 AN: 235164 AF XY: 0.0749

Gnomad AFR exome AF: 0.0806

Gnomad AMR exome AF: 0.0574

Gnomad ASJ exome AF: 0.0913

Gnomad EAS exome AF: 0.000461

Gnomad FIN exome AF: 0.0495

Gnomad NFE exome AF: 0.103

Gnomad OTH exome AF: 0.0901

GnomAD4 exome AF: 0.0914 AC: 132137 AN: 1445336 Hom.: 6827 Cov.: 31 AF XY: 0.0904 AC XY: 64911 AN XY: 718340

African (AFR) AF: 0.0811 AC: 2638 AN: 32524

American (AMR) AF: 0.0600 AC: 2452 AN: 40852

Ashkenazi Jewish (ASJ) AF: 0.0886 AC: 2252 AN: 25414

East Asian (EAS) AF: 0.000304 AC: 12 AN: 39538

South Asian (SAS) AF: 0.0347 AC: 2876 AN: 82778

European-Finnish (FIN) AF: 0.0507 AC: 2697 AN: 53200

Middle Eastern (MID) AF: 0.0848 AC: 481 AN: 5672

European-Non Finnish (NFE) AF: 0.102 AC: 113258 AN: 1105678

Other (OTH) AF: 0.0917 AC: 5471 AN: 59680

GnomAD4 genome AF: 0.0841 AC: 12804 AN: 152178 Hom.: 574 Cov.: 33 AF XY: 0.0792 AC XY: 5894 AN XY: 74402

African (AFR) AF: 0.0830 AC: 3444 AN: 41512

American (AMR) AF: 0.0857 AC: 1310 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0862 AC: 299 AN: 3468

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5186

South Asian (SAS) AF: 0.0349 AC: 168 AN: 4816

European-Finnish (FIN) AF: 0.0447 AC: 473 AN: 10590

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.100 AC: 6820 AN: 67994

Other (OTH) AF: 0.0988 AC: 209 AN: 2116

Alfa AF: 0.0982 Hom.: 1235

Bravo AF: 0.0880

Asia WGS AF: 0.0210 AC: 74 AN: 3476

EpiCase AF: 0.105

EpiControl AF: 0.107

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	6.7
DANN	Benign	0.83
PhyloP100		-0.33
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00083
dbscSNV1_RF	Benign	0.060
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: rs17595424; hg19: chr4-99993869;