1-18872727-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003748.4(ALDH4A1):c.*118G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.442 in 767,614 control chromosomes in the GnomAD database, including 78,435 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.40 ( 13051 hom., cov: 32)

Exomes 𝑓: 0.45 ( 65384 hom. )

Consequence

ALDH4A1
NM_003748.4 3_prime_UTR

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.797

Publications

9 publications found

Variant links:

Genes affected

ALDH4A1 (HGNC:406): (aldehyde dehydrogenase 4 family member A1) This protein belongs to the aldehyde dehydrogenase family of proteins. This enzyme is a mitochondrial matrix NAD-dependent dehydrogenase which catalyzes the second step of the proline degradation pathway, converting pyrroline-5-carboxylate to glutamate. Deficiency of this enzyme is associated with type II hyperprolinemia, an autosomal recessive disorder characterized by accumulation of delta-1-pyrroline-5-carboxylate (P5C) and proline. Alternatively spliced transcript variants encoding different isoforms have been identified for this gene. [provided by RefSeq, Jun 2009]

ALDH4A1 Gene-Disease associations (from GenCC):

hyperprolinemia type 2
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet

ALDH4A1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 1-18872727-C-T is Benign according to our data. Variant chr1-18872727-C-T is described in ClinVar as Benign. ClinVar VariationId is 294359.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.654 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
ALDH4A1	NM_003748.4 link	c.*118G>A	3_prime_UTR_variant	Exon 15 of 15	ENST00000375341.8	NP_003739.2	P30038-1A0A024RAC7
ALDH4A1	NM_001319218.2 link	c.*118G>A	3_prime_UTR_variant	Exon 14 of 14		NP_001306147.1	P30038-3
ALDH4A1	NM_001161504.2 link	c.*118G>A	3_prime_UTR_variant	Exon 15 of 15		NP_001154976.1	P30038-2
ALDH4A1	NM_170726.3 link	c.*41+77G>A	intron_variant	Intron 15 of 15		NP_733844.1	P30038-1A0A024RAC7

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
ALDH4A1	ENST00000375341.8 link	c.*118G>A	3_prime_UTR_variant	Exon 15 of 15	1	NM_003748.4	ENSP00000364490.3	P30038-1
ALDH4A1	ENST00000538839.5 link	c.*118G>A	3_prime_UTR_variant	Exon 14 of 14	1		ENSP00000446071.1	P30038-3
ALDH4A1	ENST00000290597.9 link	c.*41+77G>A	intron_variant	Intron 15 of 15	1		ENSP00000290597.5	P30038-1
ALDH4A1	ENST00000538309.5 link	c.*118G>A	downstream_gene_variant		2		ENSP00000442988.1	P30038-2

Frequencies

GnomAD3 genomes

AF:

0.399

AC:

60633

AN:

151812

Hom.:

13035

Cov.:

show subpopulations

Gnomad AFR

AF:

0.246

Gnomad AMI

AF:

0.424

Gnomad AMR

AF:

0.523

Gnomad ASJ

AF:

0.409

Gnomad EAS

AF:

0.673

Gnomad SAS

AF:

0.594

Gnomad FIN

AF:

0.418

Gnomad MID

AF:

0.392

Gnomad NFE

AF:

0.426

Gnomad OTH

AF:

0.422

GnomAD4 exome

AF:

0.453

AC:

278636

AN:

615686

Hom.:

65384

Cov.:

AF XY:

0.458

AC XY:

149282

AN XY:

325912

show subpopulations

African (AFR)

AF:

0.236

AC:

3964

AN:

16816

American (AMR)

AF:

0.575

AC:

19523

AN:

33924

Ashkenazi Jewish (ASJ)

AF:

0.429

AC:

7063

AN:

16464

East Asian (EAS)

AF:

0.663

AC:

23380

AN:

35268

South Asian (SAS)

AF:

0.571

AC:

32995

AN:

57750

European-Finnish (FIN)

AF:

0.414

AC:

14807

AN:

35758

Middle Eastern (MID)

AF:

0.409

AC:

962

AN:

2352

European-Non Finnish (NFE)

AF:

0.420

AC:

162002

AN:

385544

Other (OTH)

AF:

0.438

AC:

13940

AN:

31810

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

6926

13851

20777

27702

34628

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2282

4564

6846

9128

11410

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.399

AC:

60679

AN:

151928

Hom.:

13051

Cov.:

AF XY:

0.408

AC XY:

30316

AN XY:

74228

show subpopulations

African (AFR)

AF:

0.246

AC:

10210

AN:

41446

American (AMR)

AF:

0.524

AC:

8013

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.409

AC:

1419

AN:

3468

East Asian (EAS)

AF:

0.673

AC:

3468

AN:

5152

South Asian (SAS)

AF:

0.593

AC:

2848

AN:

4804

European-Finnish (FIN)

AF:

0.418

AC:

4409

AN:

10544

Middle Eastern (MID)

AF:

0.384

AC:

113

AN:

294

European-Non Finnish (NFE)

AF:

0.426

AC:

28925

AN:

67920

Other (OTH)

AF:

0.421

AC:

888

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1788

3576

5363

7151

8939

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

584

1168

1752

2336

2920

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.424

Hom.:

15945

Bravo

AF:

0.399

Asia WGS

AF:

0.594

AC:

2064

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hyperprolinemia type 2

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.60

(source)

DANN

Benign

0.43

PhyloP100

-0.80

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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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