Genetic Variant ALDH1A1:c.1200+8G>T (chr9-72911950-C-A) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_000689.5(ALDH1A1):c.1200+8G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0105 in 1,613,682 control chromosomes in the GnomAD database, including 121 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 0.0068 ( 5 hom., cov: 32)

Exomes 𝑓: 0.011 ( 116 hom. )

Consequence

ALDH1A1
NM_000689.5 splice_region, intron

Scores

Splicing: ADA: 0.00007654

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.828

Publications

10 publications found

Variant links:

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]

ALDH1A1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.71).

BP6

Variant 9-72911950-C-A is Benign according to our data. Variant chr9-72911950-C-A is described in ClinVar as [Benign]. Clinvar id is 773509.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 1041 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH1A1	NM_000689.5 link	c.1200+8G>T		splice_region_variant, intron_variant	Intron 10 of 12	ENST00000297785.8	NP_000680.2	P00352V9HW83

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH1A1	ENST00000297785.8 link	c.1200+8G>T		splice_region_variant, intron_variant	Intron 10 of 12	1	NM_000689.5	ENSP00000297785.3		P00352

Frequencies

GnomAD3 genomes

AF:

0.00684

AC:

1040

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00224

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00577

Gnomad ASJ

AF:

0.00893

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00539

Gnomad FIN

AF:

0.00273

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0112

Gnomad OTH

AF:

0.00383

GnomAD2 exomes

AF:

0.00717

AC:

1799

AN:

250916

AF XY:

0.00768

show subpopulations

Gnomad AFR exome

AF:

0.00228

Gnomad AMR exome

AF:

0.00426

Gnomad ASJ exome

AF:

0.00974

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00305

Gnomad NFE exome

AF:

0.0110

Gnomad OTH exome

AF:

0.00637

GnomAD4 exome

AF:

0.0109

AC:

15946

AN:

1461434

Hom.:

116

Cov.:

AF XY:

0.0108

AC XY:

7872

AN XY:

727012

show subpopulations

African (AFR)

AF:

0.00170

AC:

AN:

33452

American (AMR)

AF:

0.00436

AC:

195

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.00930

AC:

243

AN:

26122

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39678

South Asian (SAS)

AF:

0.00586

AC:

505

AN:

86228

European-Finnish (FIN)

AF:

0.00309

AC:

165

AN:

53412

Middle Eastern (MID)

AF:

0.00330

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0128

AC:

14274

AN:

1111714

Other (OTH)

AF:

0.00805

AC:

486

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

718

1436

2153

2871

3589

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00684

AC:

1041

AN:

152248

Hom.:

Cov.:

AF XY:

0.00605

AC XY:

450

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.00224

AC:

AN:

41560

American (AMR)

AF:

0.00582

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00893

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00539

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00273

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0112

AC:

765

AN:

68014

Other (OTH)

AF:

0.00379

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

108

162

216

270

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0107

Hom.:

Bravo

AF:

0.00660

Asia WGS

AF:

0.00173

AC:

AN:

3476

EpiCase

AF:

0.0111

EpiControl

AF:

0.0129

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 18, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.71

CADD

Benign

8.4

(source)

DANN

Benign

0.68

PhyloP100

0.83

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000077

dbscSNV1_RF

Benign

0.0

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

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9-72911950-C-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over