rs2230707

Variant names:

• chr1-18876402-G-A
• rs2230707
• NM_003748.4:c.1251C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003748.4(ALDH4A1):​c.1251C>T​(p.Ala417Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.481 in 1,612,090 control chromosomes in the GnomAD database, including 188,387 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (17668 hom., cov: 33)
  • Exomes 𝑓: 0.48 (170719 hom.)
• Consequence: ALDH4A1 NM_003748.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -9.18
• Publications: 16 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 1-18876402-G-A is Benign according to our data. Variant chr1-18876402-G-A is described in ClinVar as Benign. ClinVar VariationId is 294374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-9.18 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.598 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH4A1	NM_003748.4	c.1251C>T	p.Ala417Ala	synonymous_variant	Exon 12 of 15	ENST00000375341.8	NP_003739.2
ALDH4A1	NM_170726.3	c.1251C>T	p.Ala417Ala	synonymous_variant	Exon 12 of 16		NP_733844.1
ALDH4A1	NM_001161504.2	c.1071C>T	p.Ala357Ala	synonymous_variant	Exon 12 of 15		NP_001154976.1
ALDH4A1	NM_001319218.2	c.1185+806C>T		intron_variant	Intron 11 of 13		NP_001306147.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH4A1	ENST00000375341.8	c.1251C>T	p.Ala417Ala	synonymous_variant	Exon 12 of 15	1	NM_003748.4	ENSP00000364490.3
ALDH4A1	ENST00000290597.9	c.1251C>T	p.Ala417Ala	synonymous_variant	Exon 12 of 16	1		ENSP00000290597.5
ALDH4A1	ENST00000538839.5	c.1185+806C>T		intron_variant	Intron 11 of 13	1		ENSP00000446071.1
ALDH4A1	ENST00000538309.5	c.1071C>T	p.Ala357Ala	synonymous_variant	Exon 12 of 15	2		ENSP00000442988.1

Frequencies

GnomAD3 genomes AF: 0.477 AC: 72520 AN: 151914 Hom.: 17651 Cov.: 33

Gnomad AFR AF: 0.436

Gnomad AMI AF: 0.598

Gnomad AMR AF: 0.605

Gnomad ASJ AF: 0.501

Gnomad EAS AF: 0.615

Gnomad SAS AF: 0.501

Gnomad FIN AF: 0.426

Gnomad MID AF: 0.494

Gnomad NFE AF: 0.466

Gnomad OTH AF: 0.503

GnomAD2 exomes AF: 0.512 AC: 127294 AN: 248752 AF XY: 0.504

Gnomad AFR exome AF: 0.440

Gnomad AMR exome AF: 0.693

Gnomad ASJ exome AF: 0.500

Gnomad EAS exome AF: 0.608

Gnomad FIN exome AF: 0.435

Gnomad NFE exome AF: 0.470

Gnomad OTH exome AF: 0.515

GnomAD4 exome AF: 0.481 AC: 702251 AN: 1460058 Hom.: 170719 Cov.: 53 AF XY: 0.481 AC XY: 349125 AN XY: 726254

African (AFR) AF: 0.432 AC: 14464 AN: 33452

American (AMR) AF: 0.687 AC: 30625 AN: 44606

Ashkenazi Jewish (ASJ) AF: 0.497 AC: 12972 AN: 26112

East Asian (EAS) AF: 0.625 AC: 24797 AN: 39672

South Asian (SAS) AF: 0.499 AC: 43007 AN: 86158

European-Finnish (FIN) AF: 0.436 AC: 23038 AN: 52836

Middle Eastern (MID) AF: 0.482 AC: 2753 AN: 5710

European-Non Finnish (NFE) AF: 0.469 AC: 521296 AN: 1111186

Other (OTH) AF: 0.486 AC: 29299 AN: 60326

GnomAD4 genome AF: 0.477 AC: 72594 AN: 152032 Hom.: 17668 Cov.: 33 AF XY: 0.481 AC XY: 35757 AN XY: 74318

African (AFR) AF: 0.436 AC: 18070 AN: 41448

American (AMR) AF: 0.606 AC: 9262 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.501 AC: 1738 AN: 3470

East Asian (EAS) AF: 0.616 AC: 3175 AN: 5158

South Asian (SAS) AF: 0.499 AC: 2405 AN: 4816

European-Finnish (FIN) AF: 0.426 AC: 4505 AN: 10586

Middle Eastern (MID) AF: 0.493 AC: 145 AN: 294

European-Non Finnish (NFE) AF: 0.466 AC: 31682 AN: 67962

Other (OTH) AF: 0.505 AC: 1068 AN: 2114

Alfa AF: 0.477 Hom.: 44628

Bravo AF: 0.492

Asia WGS AF: 0.557 AC: 1940 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 02, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.018
DANN	Benign	0.82
PhyloP100		-9.2
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2230707; hg19: chr1-19202896; COSMIC: COSV51891838;