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 (★★). Synonymous variant affecting the same amino acid position (i.e. A417A) has been classified as Uncertain significance.

• 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: G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003748.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH4A1	NM_003748.4	MANE Select	c.1251C>T	p.Ala417Ala	synonymous	Exon 12 of 15	NP_003739.2
	ALDH4A1	NM_170726.3		c.1251C>T	p.Ala417Ala	synonymous	Exon 12 of 16	NP_733844.1	P30038-1
	ALDH4A1	NM_001161504.2		c.1071C>T	p.Ala357Ala	synonymous	Exon 12 of 15	NP_001154976.1	P30038-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH4A1	ENST00000375341.8	TSL:1 MANE Select	c.1251C>T	p.Ala417Ala	synonymous	Exon 12 of 15	ENSP00000364490.3	P30038-1
	ALDH4A1	ENST00000290597.9	TSL:1	c.1251C>T	p.Ala417Ala	synonymous	Exon 12 of 16	ENSP00000290597.5	P30038-1
	ALDH4A1	ENST00000538839.5	TSL:1	c.1185+806C>T		intron	N/A	ENSP00000446071.1	P30038-3

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Hyperprolinemia type 2 (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

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;