chr9-38395941-A-G

Variant names:

• chr9-38395941-A-G
• rs766769500
• NM_000692.5:c.193A>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000692.5(ALDH1B1):​c.193A>G​(p.Ile65Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,594 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. I65I) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ALDH1B1 NM_000692.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.42

Genes affected

ALDH1B1 (HGNC:407): (aldehyde dehydrogenase 1 family member B1) This protein belongs to the aldehyde dehydrogenases family of proteins. Aldehyde dehydrogenase is the second enzyme of the major oxidative pathway of alcohol metabolism. This gene does not contain introns in the coding sequence. The variation of this locus may affect the development of alcohol-related problems. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40063053).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH1B1	NM_000692.5	c.193A>G	p.Ile65Val	missense_variant	Exon 2 of 2	ENST00000377698.4	NP_000683.3
ALDH1B1	XM_011517802.3	c.334A>G	p.Ile112Val	missense_variant	Exon 2 of 2		XP_011516104.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH1B1	ENST00000377698.4	c.193A>G	p.Ile65Val	missense_variant	Exon 2 of 2	1	NM_000692.5	ENSP00000366927.3
ALDH1B1	ENST00000635162.1	c.193A>G	p.Ile65Val	missense_variant	Exon 3 of 3	3		ENSP00000489053.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 251042 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135732

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461594 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727118

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 17, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.193A>G (p.I65V) alteration is located in exon 2 (coding exon 1) of the ALDH1B1 gene. This alteration results from a A to G substitution at nucleotide position 193, causing the isoleucine (I) at amino acid position 65 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	0.12
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.022	.;T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.089
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.71	T;D
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.40	T;T
MetaSVM	Benign	-0.63	T
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.78	N;.
REVEL	Benign	0.26
Sift	Benign	0.073	T;.
Sift4G	Benign	0.067	T;T
Vest4		0.31
MutPred		0.77		Gain of disorder (P = 0.0681);Gain of disorder (P = 0.0681);
MVP		0.60
MPC		0.080
ClinPred		0.19	T
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
gMVP		0.54

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

Publications

LitVar

Other links and lift over

dbSNP: rs766769500; hg19: chr9-38395938;