chr1-18883265-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.603+14G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00299 in 1,613,176 control chromosomes in the GnomAD database, including 138 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.016 ( 76 hom., cov: 34)

Exomes 𝑓: 0.0016 ( 62 hom. )

Consequence

ALDH4A1
NM_003748.4 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.00

Publications

5 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 links:

MIR4695 (HGNC:41573): (microRNA 4695) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

MIR4695 links:

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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=-0.76).

BP6

Variant 1-18883265-C-T is Benign according to our data. Variant chr1-18883265-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 876209.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0526 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003748.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ALDH4A1	NM_003748.4	MANE Select	c.603+14G>A	intron	N/A	NP_003739.2
ALDH4A1	NM_170726.3		c.603+14G>A	intron	N/A	NP_733844.1	P30038-1
ALDH4A1	NM_001319218.2		c.603+14G>A	intron	N/A	NP_001306147.1	P30038-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ALDH4A1	ENST00000375341.8	TSL:1 MANE Select	c.603+14G>A	intron	N/A	ENSP00000364490.3	P30038-1
ALDH4A1	ENST00000290597.9	TSL:1	c.603+14G>A	intron	N/A	ENSP00000290597.5	P30038-1
ALDH4A1	ENST00000538839.5	TSL:1	c.603+14G>A	intron	N/A	ENSP00000446071.1	P30038-3

Frequencies

GnomAD3 genomes

AF:

0.0161

AC:

2450

AN:

152258

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0545

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00909

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.0148

GnomAD2 exomes

AF:

0.00425

AC:

1061

AN:

249888

AF XY:

0.00299

show subpopulations

Gnomad AFR exome

AF:

0.0568

Gnomad AMR exome

AF:

0.00304

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000187

Gnomad OTH exome

AF:

0.00279

GnomAD4 exome

AF:

0.00162

AC:

2370

AN:

1460800

Hom.:

Cov.:

AF XY:

0.00137

AC XY:

993

AN XY:

726732

show subpopulations

African (AFR)

AF:

0.0556

AC:

1863

AN:

33480

American (AMR)

AF:

0.00344

AC:

154

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52396

Middle Eastern (MID)

AF:

0.00381

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000854

AC:

AN:

1111980

Other (OTH)

AF:

0.00381

AC:

230

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

159

317

476

634

793

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

124

186

248

310

<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:

0.0161

AC:

2454

AN:

152376

Hom.:

Cov.:

AF XY:

0.0155

AC XY:

1152

AN XY:

74520

show subpopulations

African (AFR)

AF:

0.0545

AC:

2266

AN:

41594

American (AMR)

AF:

0.00908

AC:

139

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000235

AC:

AN:

68030

Other (OTH)

AF:

0.0147

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

118

237

355

474

592

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<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:

0.0106

Hom.:

Bravo

AF:

0.0183

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hyperprolinemia type 2 (2)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

5.6

(source)

DANN

Benign

0.90

PhyloP100

1.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over