Genetic Variant ALDH4A1:c.941-48C>A (chr1-18877660-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_003748.4(ALDH4A1):c.941-48C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000433 in 1,386,116 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000024 ( 0 hom. )

Consequence

ALDH4A1
NM_003748.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.839

Publications

6 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: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
ALDH4A1	NM_003748.4 link	c.941-48C>A	intron_variant	Intron 9 of 14	ENST00000375341.8	NP_003739.2	P30038-1A0A024RAC7
ALDH4A1	NM_170726.3 link	c.941-48C>A	intron_variant	Intron 9 of 15		NP_733844.1	P30038-1A0A024RAC7
ALDH4A1	NM_001319218.2 link	c.941-48C>A	intron_variant	Intron 9 of 13		NP_001306147.1	P30038-3
ALDH4A1	NM_001161504.2 link	c.761-48C>A	intron_variant	Intron 9 of 14		NP_001154976.1	P30038-2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
ALDH4A1	ENST00000375341.8 link	c.941-48C>A	intron_variant	Intron 9 of 14	1	NM_003748.4	ENSP00000364490.3	P30038-1
ALDH4A1	ENST00000290597.9 link	c.941-48C>A	intron_variant	Intron 9 of 15	1		ENSP00000290597.5	P30038-1
ALDH4A1	ENST00000538839.5 link	c.941-48C>A	intron_variant	Intron 9 of 13	1		ENSP00000446071.1	P30038-3
ALDH4A1	ENST00000538309.5 link	c.761-48C>A	intron_variant	Intron 9 of 14	2		ENSP00000442988.1	P30038-2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152018

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

215114

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000243

AC:

AN:

1234098

Hom.:

Cov.:

AF XY:

0.00000161

AC XY:

AN XY:

621198

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29188

American (AMR)

AF:

0.00

AC:

AN:

42292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24534

East Asian (EAS)

AF:

0.00

AC:

AN:

38430

South Asian (SAS)

AF:

0.00

AC:

AN:

80374

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48986

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3726

European-Non Finnish (NFE)

AF:

0.00000328

AC:

AN:

913778

Other (OTH)

AF:

0.00

AC:

AN:

52790

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152018

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74246

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41368

American (AMR)

AF:

0.00

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000194

AC:

AN:

5160

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10572

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68002

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000356

Hom.:

6982

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.89

(source)

DANN

Benign

0.75

PhyloP100

-0.84

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over