chr1-18875434-C-T

Position:

chr1-18875434-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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. 13/20 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.20

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ALDH4A1	NM_003748.4 linkuse as main transcript	c.1408G>A	p.Val470Ile	missense_variant	13/15	ENST00000375341.8
ALDH4A1	NM_170726.3 linkuse as main transcript	c.1408G>A	p.Val470Ile	missense_variant	13/16
ALDH4A1	NM_001319218.2 linkuse as main transcript	c.1255G>A	p.Val419Ile	missense_variant	12/14
ALDH4A1	NM_001161504.2 linkuse as main transcript	c.1228G>A	p.Val410Ile	missense_variant	13/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH4A1	ENST00000375341.8 linkuse as main transcript	c.1408G>A	p.Val470Ile	missense_variant	13/15	1	NM_003748.4	P1	P30038-1
ALDH4A1	ENST00000290597.9 linkuse as main transcript	c.1408G>A	p.Val470Ile	missense_variant	13/16	1		P1	P30038-1
ALDH4A1	ENST00000538839.5 linkuse as main transcript	c.1255G>A	p.Val419Ile	missense_variant	12/14	1			P30038-3
ALDH4A1	ENST00000538309.5 linkuse as main transcript	c.1228G>A	p.Val410Ile	missense_variant	13/15	2			P30038-2

Frequencies

GnomAD3 genomes

AF:

0.107

AC:

16218

AN:

152106

Hom.:

1233

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.105

AC:

26338

AN:

251474

Hom.:

2033

AF XY:

0.105

AC XY:

14252

AN XY:

135916

show subpopulations

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 SAS exome

AF:

0.0389

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.:

AF XY:

0.129

AC XY:

94110

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.0343

Gnomad4 AMR exome

AF:

0.0461

Gnomad4 ASJ exome

AF:

0.0551

Gnomad4 EAS exome

AF:

0.000353

Gnomad4 SAS exome

AF:

0.0409

Gnomad4 FIN exome

AF:

0.230

Gnomad4 NFE exome

AF:

0.148

Gnomad4 OTH exome

AF:

0.117

GnomAD4 genome

AF:

0.107

AC:

16214

AN:

152224

Hom.:

1232

Cov.:

AF XY:

0.109

AC XY:

8093

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.0376

Gnomad4 AMR

AF:

0.0756

Gnomad4 ASJ

AF:

0.0524

Gnomad4 EAS

AF:

0.00155

Gnomad4 SAS

AF:

0.0353

Gnomad4 FIN

AF:

0.244

Gnomad4 NFE

AF:

0.151

Gnomad4 OTH

AF:

0.0829

Alfa

AF:

0.130

Hom.:

2642

Bravo

AF:

0.0900

TwinsUK

AF:

0.146

AC:

540

ALSPAC

AF:

0.143

AC:

552

ESP6500AA

AF:

0.0411

AC:

181

ESP6500EA

AF:

0.148

AC:

1276

ExAC

AF:

0.104

AC:

12671

Asia WGS

AF:

0.0210

AC:

AN:

3478

EpiCase

AF:

0.134

EpiControl

AF:

0.127

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hyperprolinemia type 2

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

ALDH4A1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 07, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.074

T;.;T;.

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.095

FATHMM_MKL

Benign

0.23

LIST_S2

Pathogenic

0.98

.;D;D;D

MetaRNN

Benign

0.0017

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.90

N;.;N;.

MutationTaster

Benign

0.00028

P;P;P;P

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.25

N;N;N;N

REVEL

Benign

0.12

Sift

Benign

0.28

T;T;T;T

Sift4G

Benign

0.60

T;T;T;T

Polyphen

0.031

B;.;B;.

Vest4

0.13

MPC

0.084

ClinPred

0.012

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.21

gMVP

0.32

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over