rs2230709

Variant names:

• chr1-18875434-C-T
• rs2230709
• NM_003748.4:c.1408G>A
• ALDH4A1 p.Val470Ile

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003748.4(ALDH4A1):​c.1408G>A​(p.Val470Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.13 in 1,614,076 control chromosomes in the GnomAD database, including 15,735 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1232 hom., cov: 33)
  • Exomes 𝑓: 0.13 (14503 hom.)
• Consequence: ALDH4A1 NM_003748.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.20
• 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: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017163455).
• BP6: Variant 1-18875434-C-T is Benign according to our data. Variant chr1-18875434-C-T is described in ClinVar as Benign. ClinVar VariationId is 294367.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.149 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.1408G>A	p.Val470Ile	missense	Exon 13 of 15	NP_003739.2
	ALDH4A1	NM_170726.3		c.1408G>A	p.Val470Ile	missense	Exon 13 of 16	NP_733844.1	P30038-1
	ALDH4A1	NM_001319218.2		c.1255G>A	p.Val419Ile	missense	Exon 12 of 14	NP_001306147.1	P30038-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH4A1	ENST00000375341.8	TSL:1 MANE Select	c.1408G>A	p.Val470Ile	missense	Exon 13 of 15	ENSP00000364490.3	P30038-1
	ALDH4A1	ENST00000290597.9	TSL:1	c.1408G>A	p.Val470Ile	missense	Exon 13 of 16	ENSP00000290597.5	P30038-1
	ALDH4A1	ENST00000538839.5	TSL:1	c.1255G>A	p.Val419Ile	missense	Exon 12 of 14	ENSP00000446071.1	P30038-3

Frequencies

GnomAD3 genomes AF: 0.107 AC: 16218 AN: 152106 Hom.: 1233 Cov.: 33

Gnomad AFR AF: 0.0378

Gnomad AMI AF: 0.0713

Gnomad AMR AF: 0.0759

Gnomad ASJ AF: 0.0524

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0348

Gnomad FIN AF: 0.244

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.152

Gnomad OTH AF: 0.0838

GnomAD2 exomes AF: 0.105 AC: 26338 AN: 251474 AF XY: 0.105

Gnomad AFR exome AF: 0.0384

Gnomad AMR exome AF: 0.0452

Gnomad ASJ exome AF: 0.0519

Gnomad EAS exome AF: 0.000544

Gnomad FIN exome AF: 0.232

Gnomad NFE exome AF: 0.147

Gnomad OTH exome AF: 0.106

GnomAD4 exome AF: 0.132 AC: 192852 AN: 1461852 Hom.: 14503 Cov.: 33 AF XY: 0.129 AC XY: 94110 AN XY: 727224

African (AFR) AF: 0.0343 AC: 1149 AN: 33480

American (AMR) AF: 0.0461 AC: 2063 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0551 AC: 1441 AN: 26136

East Asian (EAS) AF: 0.000353 AC: 14 AN: 39700

South Asian (SAS) AF: 0.0409 AC: 3525 AN: 86258

European-Finnish (FIN) AF: 0.230 AC: 12292 AN: 53410

Middle Eastern (MID) AF: 0.0392 AC: 226 AN: 5768

European-Non Finnish (NFE) AF: 0.148 AC: 165062 AN: 1111982

Other (OTH) AF: 0.117 AC: 7080 AN: 60396

GnomAD4 genome AF: 0.107 AC: 16214 AN: 152224 Hom.: 1232 Cov.: 33 AF XY: 0.109 AC XY: 8093 AN XY: 74428

African (AFR) AF: 0.0376 AC: 1563 AN: 41552

American (AMR) AF: 0.0756 AC: 1157 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0524 AC: 182 AN: 3470

East Asian (EAS) AF: 0.00155 AC: 8 AN: 5170

South Asian (SAS) AF: 0.0353 AC: 170 AN: 4818

European-Finnish (FIN) AF: 0.244 AC: 2587 AN: 10610

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.151 AC: 10300 AN: 67988

Other (OTH) AF: 0.0829 AC: 175 AN: 2110

Alfa AF: 0.128 Hom.: 3551

Bravo AF: 0.0900

Asia WGS AF: 0.0210 AC: 74 AN: 3478

EpiCase AF: 0.134

EpiControl AF: 0.127

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Hyperprolinemia type 2 (2)
-	-	1	ALDH4A1-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.074	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.095
FATHMM_MKL	Benign	0.23	N
LIST_S2	Pathogenic	0.98	D
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.90	N
PhyloP100		2.2
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.12
Sift	Benign	0.28	T
Sift4G	Benign	0.60	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.21
gMVP		0.32
Mutation Taster		=95/5	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2230709;

hg19: chr1-19201928;

COSMIC: COSV51892342;