dbSNP rs2230708: ALDH4A1:p.Asp460Asp (chr1-18875462-A-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_003748.4(ALDH4A1):c.1380T>C(p.Asp460Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.724 in 1,613,800 control chromosomes in the GnomAD database, including 423,345 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.71 ( 38916 hom., cov: 31)

Exomes 𝑓: 0.72 ( 384429 hom. )

Consequence

ALDH4A1
NM_003748.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -1.31

Publications

22 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: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics

ALDH4A1 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_003748.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BP6

Variant 1-18875462-A-G is Benign according to our data. Variant chr1-18875462-A-G is described in ClinVar as Benign. ClinVar VariationId is 294369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.31 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.781 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	HGVSp	Effect	Exon Rank	Protein	UniProt
ALDH4A1	NM_003748.4	MANE Select	c.1380T>C	p.Asp460Asp	synonymous	Exon 13 of 15	NP_003739.2
ALDH4A1	NM_170726.3		c.1380T>C	p.Asp460Asp	synonymous	Exon 13 of 16	NP_733844.1	P30038-1
ALDH4A1	NM_001319218.2		c.1227T>C	p.Asp409Asp	synonymous	Exon 12 of 14	NP_001306147.1	P30038-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ALDH4A1	ENST00000375341.8	TSL:1 MANE Select	c.1380T>C	p.Asp460Asp	synonymous	Exon 13 of 15	ENSP00000364490.3	P30038-1
ALDH4A1	ENST00000290597.9	TSL:1	c.1380T>C	p.Asp460Asp	synonymous	Exon 13 of 16	ENSP00000290597.5	P30038-1
ALDH4A1	ENST00000538839.5	TSL:1	c.1227T>C	p.Asp409Asp	synonymous	Exon 12 of 14	ENSP00000446071.1	P30038-3

Frequencies

GnomAD3 genomes

AF:

0.715

AC:

108516

AN:

151872

Hom.:

38866

Cov.:

show subpopulations

Gnomad AFR

AF:

0.684

Gnomad AMI

AF:

0.788

Gnomad AMR

AF:

0.792

Gnomad ASJ

AF:

0.719

Gnomad EAS

AF:

0.722

Gnomad SAS

AF:

0.766

Gnomad FIN

AF:

0.675

Gnomad MID

AF:

0.731

Gnomad NFE

AF:

0.715

Gnomad OTH

AF:

0.734

GnomAD2 exomes

AF:

0.732

AC:

184101

AN:

251454

AF XY:

0.732

show subpopulations

Gnomad AFR exome

AF:

0.688

Gnomad AMR exome

AF:

0.818

Gnomad ASJ exome

AF:

0.719

Gnomad EAS exome

AF:

0.711

Gnomad FIN exome

AF:

0.682

Gnomad NFE exome

AF:

0.719

Gnomad OTH exome

AF:

0.744

GnomAD4 exome

AF:

0.725

AC:

1059164

AN:

1461810

Hom.:

384429

Cov.:

AF XY:

0.725

AC XY:

527322

AN XY:

727222

show subpopulations

African (AFR)

AF:

0.679

AC:

22717

AN:

33478

American (AMR)

AF:

0.820

AC:

36664

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.722

AC:

18881

AN:

26134

East Asian (EAS)

AF:

0.727

AC:

28862

AN:

39696

South Asian (SAS)

AF:

0.754

AC:

65038

AN:

86258

European-Finnish (FIN)

AF:

0.683

AC:

36497

AN:

53408

Middle Eastern (MID)

AF:

0.748

AC:

4311

AN:

5762

European-Non Finnish (NFE)

AF:

0.722

AC:

802834

AN:

1111966

Other (OTH)

AF:

0.718

AC:

43360

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

18509

37018

55527

74036

92545

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20054

40108

60162

80216

100270

<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:

0.715

AC:

108625

AN:

151990

Hom.:

38916

Cov.:

AF XY:

0.716

AC XY:

53175

AN XY:

74296

show subpopulations

African (AFR)

AF:

0.685

AC:

28379

AN:

41440

American (AMR)

AF:

0.792

AC:

12117

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.719

AC:

2494

AN:

3470

East Asian (EAS)

AF:

0.722

AC:

3706

AN:

5136

South Asian (SAS)

AF:

0.765

AC:

3691

AN:

4824

European-Finnish (FIN)

AF:

0.675

AC:

7145

AN:

10580

Middle Eastern (MID)

AF:

0.735

AC:

216

AN:

294

European-Non Finnish (NFE)

AF:

0.716

AC:

48606

AN:

67932

Other (OTH)

AF:

0.735

AC:

1552

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1642

3283

4925

6566

8208

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

842

1684

2526

3368

4210

<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:

0.719

Hom.:

83439

Bravo

AF:

0.723

Asia WGS

AF:

0.732

AC:

2549

AN:

3478

EpiCase

AF:

0.730

EpiControl

AF:

0.733

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hyperprolinemia type 2 (3)

not specified (2)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.030

(source)

DANN

Benign

0.49

PhyloP100

-1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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