rs146450609

Positions:

chr1-18902477-G-A

Variant summary

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

The NM_003748.4(ALDH4A1):c.47C>T(p.Pro16Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0283 in 1,449,494 control chromosomes in the GnomAD database, including 689 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.024 ( 54 hom., cov: 32)

Exomes 𝑓: 0.029 ( 635 hom. )

Consequence

ALDH4A1
NM_003748.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.56

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:

ALDH4A1 (HGNC:):

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=0.004030764).

BP6

Variant 1-18902477-G-A is Benign according to our data. Variant chr1-18902477-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 471330.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-18902477-G-A is described in Lovd as [Likely_benign].

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0549 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALDH4A1	NM_003748.4 linkuse as main transcript	c.47C>T	p.Pro16Leu	missense_variant	1/15	ENST00000375341.8	NP_003739.2	P30038-1A0A024RAC7
ALDH4A1	NM_170726.3 linkuse as main transcript	c.47C>T	p.Pro16Leu	missense_variant	1/16		NP_733844.1	P30038-1A0A024RAC7
ALDH4A1	NM_001319218.2 linkuse as main transcript	c.47C>T	p.Pro16Leu	missense_variant	1/14		NP_001306147.1	P30038-3
LOC124903866	XR_007065519.1 linkuse as main transcript	n.140+225G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ALDH4A1	ENST00000375341.8 linkuse as main transcript	c.47C>T	p.Pro16Leu	missense_variant	1/15	1	NM_003748.4	ENSP00000364490.3	P30038-1
ALDH4A1	ENST00000290597.9 linkuse as main transcript	c.47C>T	p.Pro16Leu	missense_variant	1/16	1		ENSP00000290597.5	P30038-1
ALDH4A1	ENST00000538839.5 linkuse as main transcript	c.47C>T	p.Pro16Leu	missense_variant	1/14	1		ENSP00000446071.1	P30038-3
ALDH4A1	ENST00000432718.1 linkuse as main transcript	c.47C>T	p.Pro16Leu	missense_variant	1/6	3			Q5TF55

Frequencies

GnomAD3 genomes

AF:

0.0245

AC:

3726

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0103

Gnomad AMI

AF:

0.0241

Gnomad AMR

AF:

0.0301

Gnomad ASJ

AF:

0.0438

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0112

Gnomad FIN

AF:

0.0394

Gnomad MID

AF:

0.0573

Gnomad NFE

AF:

0.0309

Gnomad OTH

AF:

0.0349

GnomAD3 exomes

AF:

0.0185

AC:

1464

AN:

79020

Hom.:

AF XY:

0.0185

AC XY:

827

AN XY:

44712

show subpopulations

Gnomad AFR exome

AF:

0.00797

Gnomad AMR exome

AF:

0.0166

Gnomad ASJ exome

AF:

0.0239

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00961

Gnomad FIN exome

AF:

0.0251

Gnomad NFE exome

AF:

0.0243

Gnomad OTH exome

AF:

0.0315

GnomAD4 exome

AF:

0.0288

AC:

37361

AN:

1297244

Hom.:

635

Cov.:

AF XY:

0.0285

AC XY:

18171

AN XY:

637704

show subpopulations

Gnomad4 AFR exome

AF:

0.0106

Gnomad4 AMR exome

AF:

0.0197

Gnomad4 ASJ exome

AF:

0.0330

Gnomad4 EAS exome

AF:

0.0000342

Gnomad4 SAS exome

AF:

0.0117

Gnomad4 FIN exome

AF:

0.0311

Gnomad4 NFE exome

AF:

0.0311

Gnomad4 OTH exome

AF:

0.0303

GnomAD4 genome

AF:

0.0244

AC:

3720

AN:

152250

Hom.:

Cov.:

AF XY:

0.0252

AC XY:

1872

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.0102

Gnomad4 AMR

AF:

0.0301

Gnomad4 ASJ

AF:

0.0438

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.0110

Gnomad4 FIN

AF:

0.0394

Gnomad4 NFE

AF:

0.0309

Gnomad4 OTH

AF:

0.0345

Alfa

AF:

0.0262

Hom.:

Bravo

AF:

0.0242

TwinsUK

AF:

0.0289

AC:

107

ALSPAC

AF:

0.0337

AC:

130

ExAC

AF:

0.00907

AC:

204

Asia WGS

AF:

0.00606

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hyperprolinemia type 2

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.022

T;.;T;.

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.69

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.75

.;T;T;T

MetaRNN

Benign

0.0040

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

L;L;L;.

PrimateAI

Uncertain

0.56

PROVEAN

Benign

0.070

N;N;N;N

REVEL

Benign

0.15

Sift

Benign

0.072

T;T;T;D

Sift4G

Benign

0.13

T;T;T;.

Polyphen

0.018

B;.;B;.

Vest4

0.23

MPC

0.10

ClinPred

0.019

GERP RS

3.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.036

gMVP

0.40

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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