1-18876423-T-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_003748.4(ALDH4A1):c.1230A>G(p.Ser410Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.695 in 1,608,858 control chromosomes in the GnomAD database, including 391,287 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.64 ( 31993 hom., cov: 32)

Exomes 𝑓: 0.70 ( 359294 hom. )

Consequence

ALDH4A1
NM_003748.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -6.07

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BP6

Variant 1-18876423-T-C is Benign according to our data. Variant chr1-18876423-T-C is described in ClinVar as [Benign]. Clinvar id is 294375.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-18876423-T-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-6.07 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.74 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH4A1	NM_003748.4 link	c.1230A>G	p.Ser410Ser	synonymous_variant	Exon 12 of 15	ENST00000375341.8	NP_003739.2	P30038-1A0A024RAC7
ALDH4A1	NM_170726.3 link	c.1230A>G	p.Ser410Ser	synonymous_variant	Exon 12 of 16		NP_733844.1	P30038-1A0A024RAC7
ALDH4A1	NM_001161504.2 link	c.1050A>G	p.Ser350Ser	synonymous_variant	Exon 12 of 15		NP_001154976.1	P30038-2
ALDH4A1	NM_001319218.2 link	c.1185+785A>G		intron_variant	Intron 11 of 13		NP_001306147.1	P30038-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ALDH4A1	ENST00000375341.8 link	c.1230A>G	p.Ser410Ser	synonymous_variant	Exon 12 of 15	1	NM_003748.4	ENSP00000364490.3	P30038-1
ALDH4A1	ENST00000290597.9 link	c.1230A>G	p.Ser410Ser	synonymous_variant	Exon 12 of 16	1		ENSP00000290597.5	P30038-1
ALDH4A1	ENST00000538839.5 link	c.1185+785A>G		intron_variant	Intron 11 of 13	1		ENSP00000446071.1	P30038-3
ALDH4A1	ENST00000538309.5 link	c.1050A>G	p.Ser350Ser	synonymous_variant	Exon 12 of 15	2		ENSP00000442988.1	P30038-2

Frequencies

GnomAD3 genomes

AF:

0.643

AC:

97343

AN:

151436

Hom.:

31974

Cov.:

show subpopulations

Gnomad AFR

AF:

0.486

Gnomad AMI

AF:

0.789

Gnomad AMR

AF:

0.750

Gnomad ASJ

AF:

0.679

Gnomad EAS

AF:

0.722

Gnomad SAS

AF:

0.748

Gnomad FIN

AF:

0.650

Gnomad MID

AF:

0.657

Gnomad NFE

AF:

0.695

Gnomad OTH

AF:

0.678

GnomAD3 exomes

AF:

0.699

AC:

170871

AN:

244574

Hom.:

60119

AF XY:

0.701

AC XY:

92938

AN XY:

132564

show subpopulations

Gnomad AFR exome

AF:

0.484

Gnomad AMR exome

AF:

0.795

Gnomad ASJ exome

AF:

0.689

Gnomad EAS exome

AF:

0.712

Gnomad SAS exome

AF:

0.742

Gnomad FIN exome

AF:

0.651

Gnomad NFE exome

AF:

0.695

Gnomad OTH exome

AF:

0.711

GnomAD4 exome

AF:

0.701

AC:

1021107

AN:

1457304

Hom.:

359294

Cov.:

AF XY:

0.702

AC XY:

508675

AN XY:

724836

show subpopulations

Gnomad4 AFR exome

AF:

0.474

Gnomad4 AMR exome

AF:

0.796

Gnomad4 ASJ exome

AF:

0.691

Gnomad4 EAS exome

AF:

0.729

Gnomad4 SAS exome

AF:

0.738

Gnomad4 FIN exome

AF:

0.654

Gnomad4 NFE exome

AF:

0.703

Gnomad4 OTH exome

AF:

0.684

GnomAD4 genome

AF:

0.643

AC:

97417

AN:

151554

Hom.:

31993

Cov.:

AF XY:

0.646

AC XY:

47826

AN XY:

74026

show subpopulations

Gnomad4 AFR

AF:

0.486

Gnomad4 AMR

AF:

0.751

Gnomad4 ASJ

AF:

0.679

Gnomad4 EAS

AF:

0.722

Gnomad4 SAS

AF:

0.747

Gnomad4 FIN

AF:

0.650

Gnomad4 NFE

AF:

0.695

Gnomad4 OTH

AF:

0.679

Alfa

AF:

0.659

Hom.:

6167

Bravo

AF:

0.644

Asia WGS

AF:

0.707

AC:

2460

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hyperprolinemia type 2

Benign:3

Jan 13, 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. -

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:2

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:2

Apr 26, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

-0.76

CADD

Benign

0.091

DANN

Benign

0.72

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