chr1-18875462-A-G

Variant names:

• chr1-18875462-A-G
• rs2230708
• NM_003748.4:c.1380T>C

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.1380T>C​(p.Asp460Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.724 in 1,613,800 control chromosomes in the GnomAD database, including 423,345 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.71 (38916 hom., cov: 31)
  • Exomes 𝑓: 0.72 (384429 hom.)
• Consequence: ALDH4A1 NM_003748.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.31
• Publications: 22 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=-0.89).
• BP6: Variant 1-18875462-A-G is Benign according to our data. Variant chr1-18875462-A-G is described in CliVar as Benign. Clinvar id is 294369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-18875462-A-G is described in CliVar as Benign. Clinvar id is 294369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-18875462-A-G is described in CliVar as Benign. Clinvar id is 294369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-18875462-A-G is described in CliVar as Benign. Clinvar id is 294369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-18875462-A-G is described in CliVar as Benign. Clinvar id is 294369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-18875462-A-G is described in CliVar as Benign. Clinvar id is 294369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-18875462-A-G is described in CliVar as Benign. Clinvar id is 294369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-18875462-A-G is described in CliVar as Benign. Clinvar id is 294369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-18875462-A-G is described in CliVar as Benign. Clinvar id is 294369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-18875462-A-G is described in CliVar as Benign. Clinvar id is 294369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-18875462-A-G is described in CliVar as Benign. Clinvar id is 294369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-18875462-A-G is described in CliVar as Benign. Clinvar id is 294369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-18875462-A-G is described in CliVar as Benign. Clinvar id is 294369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-18875462-A-G is described in CliVar as Benign. Clinvar id is 294369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-18875462-A-G is described in CliVar as Benign. Clinvar id is 294369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-18875462-A-G is described in CliVar as Benign. Clinvar id is 294369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-18875462-A-G is described in CliVar as Benign. Clinvar id is 294369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-18875462-A-G is described in CliVar as Benign. Clinvar id is 294369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-18875462-A-G is described in CliVar as Benign. Clinvar id is 294369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-18875462-A-G is described in CliVar as Benign. Clinvar id is 294369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-18875462-A-G is described in CliVar as Benign. Clinvar id is 294369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-18875462-A-G is described in CliVar as Benign. Clinvar id is 294369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-18875462-A-G is described in CliVar as Benign. Clinvar id is 294369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-18875462-A-G is described in CliVar as Benign. Clinvar id is 294369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-18875462-A-G is described in CliVar as Benign. Clinvar id is 294369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-18875462-A-G is described in CliVar as Benign. Clinvar id is 294369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.31 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.781 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH4A1	NM_003748.4	c.1380T>C	p.Asp460Asp	synonymous_variant	Exon 13 of 15	ENST00000375341.8	NP_003739.2
ALDH4A1	NM_170726.3	c.1380T>C	p.Asp460Asp	synonymous_variant	Exon 13 of 16		NP_733844.1
ALDH4A1	NM_001319218.2	c.1227T>C	p.Asp409Asp	synonymous_variant	Exon 12 of 14		NP_001306147.1
ALDH4A1	NM_001161504.2	c.1200T>C	p.Asp400Asp	synonymous_variant	Exon 13 of 15		NP_001154976.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH4A1	ENST00000375341.8	c.1380T>C	p.Asp460Asp	synonymous_variant	Exon 13 of 15	1	NM_003748.4	ENSP00000364490.3
ALDH4A1	ENST00000290597.9	c.1380T>C	p.Asp460Asp	synonymous_variant	Exon 13 of 16	1		ENSP00000290597.5
ALDH4A1	ENST00000538839.5	c.1227T>C	p.Asp409Asp	synonymous_variant	Exon 12 of 14	1		ENSP00000446071.1
ALDH4A1	ENST00000538309.5	c.1200T>C	p.Asp400Asp	synonymous_variant	Exon 13 of 15	2		ENSP00000442988.1

Frequencies

GnomAD3 genomes AF: 0.715 AC: 108516 AN: 151872 Hom.: 38866 Cov.: 31

Gnomad AFR AF: 0.684

Gnomad AMI AF: 0.788

Gnomad AMR AF: 0.792

Gnomad ASJ AF: 0.719

Gnomad EAS AF: 0.722

Gnomad SAS AF: 0.766

Gnomad FIN AF: 0.675

Gnomad MID AF: 0.731

Gnomad NFE AF: 0.715

Gnomad OTH AF: 0.734

GnomAD2 exomes AF: 0.732 AC: 184101 AN: 251454 AF XY: 0.732

Gnomad AFR exome AF: 0.688

Gnomad AMR exome AF: 0.818

Gnomad ASJ exome AF: 0.719

Gnomad EAS exome AF: 0.711

Gnomad FIN exome AF: 0.682

Gnomad NFE exome AF: 0.719

Gnomad OTH exome AF: 0.744

GnomAD4 exome AF: 0.725 AC: 1059164 AN: 1461810 Hom.: 384429 Cov.: 67 AF XY: 0.725 AC XY: 527322 AN XY: 727222

African (AFR) AF: 0.679 AC: 22717 AN: 33478

American (AMR) AF: 0.820 AC: 36664 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.722 AC: 18881 AN: 26134

East Asian (EAS) AF: 0.727 AC: 28862 AN: 39696

South Asian (SAS) AF: 0.754 AC: 65038 AN: 86258

European-Finnish (FIN) AF: 0.683 AC: 36497 AN: 53408

Middle Eastern (MID) AF: 0.748 AC: 4311 AN: 5762

European-Non Finnish (NFE) AF: 0.722 AC: 802834 AN: 1111966

Other (OTH) AF: 0.718 AC: 43360 AN: 60388

GnomAD4 genome AF: 0.715 AC: 108625 AN: 151990 Hom.: 38916 Cov.: 31 AF XY: 0.716 AC XY: 53175 AN XY: 74296

African (AFR) AF: 0.685 AC: 28379 AN: 41440

American (AMR) AF: 0.792 AC: 12117 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.719 AC: 2494 AN: 3470

East Asian (EAS) AF: 0.722 AC: 3706 AN: 5136

South Asian (SAS) AF: 0.765 AC: 3691 AN: 4824

European-Finnish (FIN) AF: 0.675 AC: 7145 AN: 10580

Middle Eastern (MID) AF: 0.735 AC: 216 AN: 294

European-Non Finnish (NFE) AF: 0.716 AC: 48606 AN: 67932

Other (OTH) AF: 0.735 AC: 1552 AN: 2112

Alfa AF: 0.719 Hom.: 83439

Bravo AF: 0.723

Asia WGS AF: 0.732 AC: 2549 AN: 3478

EpiCase AF: 0.730

EpiControl AF: 0.733

ClinVar

Significance: Benign

Submissions summary: Benign:6

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 specified Benign:2

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

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

Significance: Benign

Review Status: no assertion criteria provided

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	-0.89
CADD	Benign	0.030
DANN	Benign	0.49
PhyloP100		-1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Mutation Taster		=100/0	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: rs2230708; hg19: chr1-19201956; COSMIC: COSV108075515;