Genetic Variant ALDH4A1:c.249+22A>G (chr1-18889340-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003748.4(ALDH4A1):c.249+22A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.961 in 1,549,528 control chromosomes in the GnomAD database, including 716,232 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.97 ( 71521 hom., cov: 32)

Exomes 𝑓: 0.96 ( 644711 hom. )

Consequence

ALDH4A1
NM_003748.4 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.521

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.95).

BP6

Variant 1-18889340-T-C is Benign according to our data. Variant chr1-18889340-T-C is described in ClinVar as [Benign]. Clinvar id is 1188912.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.985 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
ALDH4A1	NM_003748.4 link	c.249+22A>G	intron_variant	Intron 3 of 14	ENST00000375341.8	NP_003739.2	P30038-1A0A024RAC7
ALDH4A1	NM_170726.3 link	c.249+22A>G	intron_variant	Intron 3 of 15		NP_733844.1	P30038-1A0A024RAC7
ALDH4A1	NM_001319218.2 link	c.249+22A>G	intron_variant	Intron 3 of 13		NP_001306147.1	P30038-3
ALDH4A1	NM_001161504.2 link	c.69+22A>G	intron_variant	Intron 3 of 14		NP_001154976.1	P30038-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH4A1	ENST00000375341.8 link	c.249+22A>G		intron_variant	Intron 3 of 14	1	NM_003748.4	ENSP00000364490.3		P30038-1

Frequencies

GnomAD3 genomes

AF:

0.969

AC:

147473

AN:

152202

Hom.:

71460

Cov.:

show subpopulations

Gnomad AFR

AF:

0.993

Gnomad AMI

AF:

0.912

Gnomad AMR

AF:

0.971

Gnomad ASJ

AF:

0.960

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

0.991

Gnomad FIN

AF:

0.952

Gnomad MID

AF:

0.949

Gnomad NFE

AF:

0.954

Gnomad OTH

AF:

0.966

GnomAD3 exomes

AF:

0.968

AC:

151510

AN:

156562

Hom.:

73331

AF XY:

0.969

AC XY:

79851

AN XY:

82370

show subpopulations

Gnomad AFR exome

AF:

0.993

Gnomad AMR exome

AF:

0.973

Gnomad ASJ exome

AF:

0.961

Gnomad EAS exome

AF:

1.00

Gnomad SAS exome

AF:

0.986

Gnomad FIN exome

AF:

0.943

Gnomad NFE exome

AF:

0.957

Gnomad OTH exome

AF:

0.959

GnomAD4 exome

AF:

0.961

AC:

1342054

AN:

1397208

Hom.:

644711

Cov.:

AF XY:

0.961

AC XY:

662730

AN XY:

689294

show subpopulations

Gnomad4 AFR exome

AF:

0.993

Gnomad4 AMR exome

AF:

0.973

Gnomad4 ASJ exome

AF:

0.958

Gnomad4 EAS exome

AF:

1.00

Gnomad4 SAS exome

AF:

0.987

Gnomad4 FIN exome

AF:

0.947

Gnomad4 NFE exome

AF:

0.956

Gnomad4 OTH exome

AF:

0.965

GnomAD4 genome

AF:

0.969

AC:

147593

AN:

152320

Hom.:

71521

Cov.:

AF XY:

0.970

AC XY:

72235

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.993

Gnomad4 AMR

AF:

0.971

Gnomad4 ASJ

AF:

0.960

Gnomad4 EAS

AF:

1.00

Gnomad4 SAS

AF:

0.991

Gnomad4 FIN

AF:

0.952

Gnomad4 NFE

AF:

0.954

Gnomad4 OTH

AF:

0.966

Alfa

AF:

0.960

Hom.:

12979

Bravo

AF:

0.971

Asia WGS

AF:

0.994

AC:

3454

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hyperprolinemia type 2

Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

-0.95

CADD

Benign

3.3

DANN

Benign

0.69

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over