NM_000689.5:c.633+7C>A

Variant names:

• chr9-72925477-G-T
• rs8187930
• NM_000689.5:c.633+7C>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000689.5(ALDH1A1):​c.633+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 0.00145 in 1,611,540 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts 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 Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0080 (14 hom., cov: 33)
  • Exomes 𝑓: 0.00077 (6 hom.)
• Consequence: ALDH1A1 NM_000689.5 splice_region, intron
• Scores: Splicing: ADA: 0.00002150
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.561
• 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 9-72925477-G-T is Benign according to our data. Variant chr9-72925477-G-T is described in ClinVar as [Benign]. Clinvar id is 711509.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00801 (1220/152262) while in subpopulation AFR AF = 0.0276 (1148/41546). AF 95% confidence interval is 0.0263. There are 14 homozygotes in GnomAd4. There are 552 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1220 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH1A1	NM_000689.5	c.633+7C>A		splice_region_variant, intron_variant	Intron 6 of 12	ENST00000297785.8	NP_000680.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH1A1	ENST00000297785.8	c.633+7C>A		splice_region_variant, intron_variant	Intron 6 of 12	1	NM_000689.5	ENSP00000297785.3

Frequencies

GnomAD3 genomes AF: 0.00806 AC: 1226 AN: 152144 Hom.: 15 Cov.: 33

Gnomad AFR AF: 0.0279

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00288

GnomAD2 exomes AF: 0.00230 AC: 571 AN: 247936 AF XY: 0.00168

Gnomad AFR exome AF: 0.0297

Gnomad AMR exome AF: 0.00213

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000444

Gnomad OTH exome AF: 0.000998

GnomAD4 exome AF: 0.000770 AC: 1123 AN: 1459278 Hom.: 6 Cov.: 30 AF XY: 0.000657 AC XY: 477 AN XY: 725878

African (AFR) AF: 0.0266 AC: 885 AN: 33280

American (AMR) AF: 0.00211 AC: 93 AN: 44036

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25966

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.000105 AC: 9 AN: 85666

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53368

Middle Eastern (MID) AF: 0.000349 AC: 2 AN: 5738

European-Non Finnish (NFE) AF: 0.0000198 AC: 22 AN: 1111248

Other (OTH) AF: 0.00186 AC: 112 AN: 60302

GnomAD4 genome AF: 0.00801 AC: 1220 AN: 152262 Hom.: 14 Cov.: 33 AF XY: 0.00741 AC XY: 552 AN XY: 74468

African (AFR) AF: 0.0276 AC: 1148 AN: 41546

American (AMR) AF: 0.00373 AC: 57 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68024

Other (OTH) AF: 0.00285 AC: 6 AN: 2108

Alfa AF: 0.00349 Hom.: 7

Bravo AF: 0.00968

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jul 16, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.20
DANN	Benign	0.68
PhyloP100		-0.56
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000022
dbscSNV1_RF	Benign	0.0020
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: rs8187930; hg19: chr9-75540393;