rs775903305

Variant names:

• chr9-72927171-T-A
• rs775903305
• NM_000689.5:c.449A>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000689.5(ALDH1A1):​c.449A>T​(p.Asn150Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,449,120 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ALDH1A1 NM_000689.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.46
• Publications: 1 publications found

Genes affected

ALDH1A1 (HGNC:402): (aldehyde dehydrogenase 1 family member A1) The protein encoded by this gene belongs to the aldehyde dehydrogenase family. Aldehyde dehydrogenase is the next enzyme after alcohol dehydrogenase in the major pathway of alcohol metabolism. There are two major aldehyde dehydrogenase isozymes in the liver, cytosolic and mitochondrial, which are encoded by distinct genes, and can be distinguished by their electrophoretic mobility, kinetic properties, and subcellular localization. This gene encodes the cytosolic isozyme. Studies in mice show that through its role in retinol metabolism, this gene may also be involved in the regulation of the metabolic responses to high-fat diet. [provided by RefSeq, Mar 2011]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000689.5. 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
	ALDH1A1	NM_000689.5	MANE Select	c.449A>T	p.Asn150Ile	missense	Exon 5 of 13	NP_000680.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH1A1	ENST00000297785.8	TSL:1 MANE Select	c.449A>T	p.Asn150Ile	missense	Exon 5 of 13	ENSP00000297785.3	P00352
	ALDH1A1	ENST00000856212.1		c.539A>T	p.Asn180Ile	missense	Exon 6 of 14	ENSP00000526271.1
	ALDH1A1	ENST00000966555.1		c.518A>T	p.Asn173Ile	missense	Exon 6 of 14	ENSP00000636614.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000412 AC: 1 AN: 242458 AF XY: 0.00000760

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000207 AC: 3 AN: 1449120 Hom.: 0 Cov.: 27 AF XY: 0.00000416 AC XY: 3 AN XY: 721448

African (AFR) AF: 0.00 AC: 0 AN: 32686

American (AMR) AF: 0.00 AC: 0 AN: 42110

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25558

East Asian (EAS) AF: 0.00 AC: 0 AN: 39556

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 84754

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53152

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5686

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1105812

Other (OTH) AF: 0.00 AC: 0 AN: 59806

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.045	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.79	D
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.087	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Uncertain	-0.090	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		7.5
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.36
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.059	T
Polyphen		0.44	B
Vest4		0.26
MutPred		0.52		Loss of solvent accessibility (P = 0.0193)
MVP		0.59
MPC		1.1
ClinPred		0.92	D
GERP RS		5.9
Varity_R		0.70
gMVP		0.78
Mutation Taster		=32/68	disease causing

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: rs775903305; hg19: chr9-75542087;