1-18877503-C-G

Variant names:

• chr1-18877503-C-G
• rs2230705
• NM_003748.4:c.1050G>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_003748.4(ALDH4A1):​c.1050G>C​(p.Ala350Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.71 in 1,607,222 control chromosomes in the GnomAD database, including 408,905 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.71 (38646 hom., cov: 33)
  • Exomes 𝑓: 0.71 (370259 hom.)
• Consequence: ALDH4A1 NM_003748.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.60
• Publications: 21 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 1-18877503-C-G is Benign according to our data. Variant chr1-18877503-C-G is described in ClinVar as Benign. ClinVar VariationId is 294382.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.6 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.715 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH4A1	NM_003748.4	c.1050G>C	p.Ala350Ala	synonymous_variant	Exon 10 of 15	ENST00000375341.8	NP_003739.2
ALDH4A1	NM_170726.3	c.1050G>C	p.Ala350Ala	synonymous_variant	Exon 10 of 16		NP_733844.1
ALDH4A1	NM_001319218.2	c.1050G>C	p.Ala350Ala	synonymous_variant	Exon 10 of 14		NP_001306147.1
ALDH4A1	NM_001161504.2	c.870G>C	p.Ala290Ala	synonymous_variant	Exon 10 of 15		NP_001154976.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH4A1	ENST00000375341.8	c.1050G>C	p.Ala350Ala	synonymous_variant	Exon 10 of 15	1	NM_003748.4	ENSP00000364490.3
ALDH4A1	ENST00000290597.9	c.1050G>C	p.Ala350Ala	synonymous_variant	Exon 10 of 16	1		ENSP00000290597.5
ALDH4A1	ENST00000538839.5	c.1050G>C	p.Ala350Ala	synonymous_variant	Exon 10 of 14	1		ENSP00000446071.1
ALDH4A1	ENST00000538309.5	c.870G>C	p.Ala290Ala	synonymous_variant	Exon 10 of 15	2		ENSP00000442988.1

Frequencies

GnomAD3 genomes AF: 0.710 AC: 107923 AN: 152036 Hom.: 38609 Cov.: 33

Gnomad AFR AF: 0.722

Gnomad AMI AF: 0.674

Gnomad AMR AF: 0.718

Gnomad ASJ AF: 0.639

Gnomad EAS AF: 0.455

Gnomad SAS AF: 0.581

Gnomad FIN AF: 0.807

Gnomad MID AF: 0.573

Gnomad NFE AF: 0.720

Gnomad OTH AF: 0.696

GnomAD2 exomes AF: 0.689 AC: 164889 AN: 239156 AF XY: 0.683

Gnomad AFR exome AF: 0.723

Gnomad AMR exome AF: 0.746

Gnomad ASJ exome AF: 0.619

Gnomad EAS exome AF: 0.449

Gnomad FIN exome AF: 0.801

Gnomad NFE exome AF: 0.719

Gnomad OTH exome AF: 0.700

GnomAD4 exome AF: 0.710 AC: 1033651 AN: 1455068 Hom.: 370259 Cov.: 76 AF XY: 0.706 AC XY: 510376 AN XY: 723282

African (AFR) AF: 0.724 AC: 24183 AN: 33402

American (AMR) AF: 0.744 AC: 32685 AN: 43910

Ashkenazi Jewish (ASJ) AF: 0.624 AC: 16226 AN: 26004

East Asian (EAS) AF: 0.456 AC: 17993 AN: 39478

South Asian (SAS) AF: 0.588 AC: 50128 AN: 85278

European-Finnish (FIN) AF: 0.799 AC: 41602 AN: 52066

Middle Eastern (MID) AF: 0.596 AC: 3329 AN: 5586

European-Non Finnish (NFE) AF: 0.727 AC: 806171 AN: 1109242

Other (OTH) AF: 0.688 AC: 41334 AN: 60102

GnomAD4 genome AF: 0.710 AC: 108017 AN: 152154 Hom.: 38646 Cov.: 33 AF XY: 0.711 AC XY: 52891 AN XY: 74388

African (AFR) AF: 0.721 AC: 29937 AN: 41500

American (AMR) AF: 0.718 AC: 10986 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.639 AC: 2219 AN: 3470

East Asian (EAS) AF: 0.456 AC: 2356 AN: 5166

South Asian (SAS) AF: 0.582 AC: 2810 AN: 4830

European-Finnish (FIN) AF: 0.807 AC: 8566 AN: 10612

Middle Eastern (MID) AF: 0.582 AC: 171 AN: 294

European-Non Finnish (NFE) AF: 0.719 AC: 48900 AN: 67964

Other (OTH) AF: 0.691 AC: 1460 AN: 2112

Alfa AF: 0.693 Hom.: 9493

Bravo AF: 0.705

Asia WGS AF: 0.520 AC: 1813 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyperprolinemia type 2 Benign:3

Jan 12, 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: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	-0.43
CADD	Benign	8.7
DANN	Benign	0.74
PhyloP100		1.6
Mutation Taster		=97/3	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: rs2230705; hg19: chr1-19203997; COSMIC: COSV51892136;