9-38396005-C-T

Variant names:

• chr9-38396005-C-T
• rs2228093
• NM_000692.5:c.257C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000692.5(ALDH1B1):​c.257C>T​(p.Ala86Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.152 in 1,613,532 control chromosomes in the GnomAD database, including 21,566 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2055 hom., cov: 34)
  • Exomes 𝑓: 0.15 (19511 hom.)
• Consequence: ALDH1B1 NM_000692.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 7.55
• Publications: 40 publications found

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]

ALDH1B1 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030218363).
• BP6: Variant 9-38396005-C-T is Benign according to our data. Variant chr9-38396005-C-T is described in ClinVar as Benign. ClinVar VariationId is 136361.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.37 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000692.5. 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
	ALDH1B1	NM_000692.5	MANE Select	c.257C>T	p.Ala86Val	missense	Exon 2 of 2	NP_000683.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH1B1	ENST00000377698.4	TSL:1 MANE Select	c.257C>T	p.Ala86Val	missense	Exon 2 of 2	ENSP00000366927.3	P30837
	ALDH1B1	ENST00000897464.1		c.257C>T	p.Ala86Val	missense	Exon 2 of 2	ENSP00000567523.1
	ALDH1B1	ENST00000897465.1		c.257C>T	p.Ala86Val	missense	Exon 2 of 2	ENSP00000567524.1

Frequencies

GnomAD3 genomes AF: 0.149 AC: 22596 AN: 152090 Hom.: 2047 Cov.: 34

Gnomad AFR AF: 0.0954

Gnomad AMI AF: 0.0921

Gnomad AMR AF: 0.231

Gnomad ASJ AF: 0.140

Gnomad EAS AF: 0.384

Gnomad SAS AF: 0.272

Gnomad FIN AF: 0.177

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.133

Gnomad OTH AF: 0.147

GnomAD2 exomes AF: 0.194 AC: 48473 AN: 250432 AF XY: 0.191

Gnomad AFR exome AF: 0.0941

Gnomad AMR exome AF: 0.327

Gnomad ASJ exome AF: 0.141

Gnomad EAS exome AF: 0.378

Gnomad FIN exome AF: 0.182

Gnomad NFE exome AF: 0.130

Gnomad OTH exome AF: 0.163

GnomAD4 exome AF: 0.153 AC: 222885 AN: 1461324 Hom.: 19511 Cov.: 101 AF XY: 0.155 AC XY: 112717 AN XY: 727000

African (AFR) AF: 0.0929 AC: 3111 AN: 33480

American (AMR) AF: 0.315 AC: 14075 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.142 AC: 3710 AN: 26132

East Asian (EAS) AF: 0.362 AC: 14361 AN: 39698

South Asian (SAS) AF: 0.254 AC: 21950 AN: 86250

European-Finnish (FIN) AF: 0.182 AC: 9644 AN: 52902

Middle Eastern (MID) AF: 0.169 AC: 977 AN: 5768

European-Non Finnish (NFE) AF: 0.131 AC: 145535 AN: 1111978

Other (OTH) AF: 0.158 AC: 9522 AN: 60394

GnomAD4 genome AF: 0.149 AC: 22622 AN: 152208 Hom.: 2055 Cov.: 34 AF XY: 0.155 AC XY: 11542 AN XY: 74406

African (AFR) AF: 0.0954 AC: 3963 AN: 41558

American (AMR) AF: 0.232 AC: 3542 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.140 AC: 485 AN: 3468

East Asian (EAS) AF: 0.384 AC: 1980 AN: 5154

South Asian (SAS) AF: 0.271 AC: 1309 AN: 4822

European-Finnish (FIN) AF: 0.177 AC: 1875 AN: 10592

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.133 AC: 9023 AN: 68004

Other (OTH) AF: 0.152 AC: 322 AN: 2114

Alfa AF: 0.140 Hom.: 5275

Bravo AF: 0.151

TwinsUK AF: 0.127 AC: 472

ALSPAC AF: 0.134 AC: 517

ESP6500AA AF: 0.107 AC: 472

ESP6500EA AF: 0.133 AC: 1143

ExAC AF: 0.185 AC: 22419

Asia WGS AF: 0.303 AC: 1051 AN: 3478

EpiCase AF: 0.128

EpiControl AF: 0.128

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.36
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.29	T
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-1.0	T
PhyloP100		7.5
PrimateAI	Uncertain	0.48	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.36
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.75
MPC		0.49
ClinPred		0.017	T
GERP RS		5.5
gMVP		0.76
Mutation Taster		=82/18	polymorphism (auto)

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: rs2228093; hg19: chr9-38396002; COSMIC: COSV66619256;