chr1-18872906-G-A

Position:

chr1-18872906-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_003748.4(ALDH4A1):c.1631C>T(p.Pro544Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00235 in 1,614,072 control chromosomes in the GnomAD database, including 79 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P544P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.013 ( 41 hom., cov: 33)

Exomes 𝑓: 0.0013 ( 38 hom. )

Consequence

ALDH4A1
NM_003748.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 9.74

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0097464025).

BP6

Variant 1-18872906-G-A is Benign according to our data. Variant chr1-18872906-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 294364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0126 (1921/152292) while in subpopulation AFR AF= 0.0419 (1741/41548). AF 95% confidence interval is 0.0403. There are 41 homozygotes in gnomad4. There are 894 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 41 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ALDH4A1	NM_003748.4 linkuse as main transcript	c.1631C>T	p.Pro544Leu	missense_variant	15/15	ENST00000375341.8
ALDH4A1	NM_170726.3 linkuse as main transcript	c.1631C>T	p.Pro544Leu	missense_variant	15/16
ALDH4A1	NM_001319218.2 linkuse as main transcript	c.1478C>T	p.Pro493Leu	missense_variant	14/14
ALDH4A1	NM_001161504.2 linkuse as main transcript	c.1451C>T	p.Pro484Leu	missense_variant	15/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH4A1	ENST00000375341.8 linkuse as main transcript	c.1631C>T	p.Pro544Leu	missense_variant	15/15	1	NM_003748.4	P1	P30038-1
ALDH4A1	ENST00000290597.9 linkuse as main transcript	c.1631C>T	p.Pro544Leu	missense_variant	15/16	1		P1	P30038-1
ALDH4A1	ENST00000538839.5 linkuse as main transcript	c.1478C>T	p.Pro493Leu	missense_variant	14/14	1			P30038-3
ALDH4A1	ENST00000538309.5 linkuse as main transcript	c.1451C>T	p.Pro484Leu	missense_variant	15/15	2			P30038-2

Frequencies

GnomAD3 genomes

AF:

0.0126

AC:

1917

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0419

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00968

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00813

GnomAD3 exomes

AF:

0.00330

AC:

829

AN:

251366

Hom.:

AF XY:

0.00232

AC XY:

315

AN XY:

135872

show subpopulations

Gnomad AFR exome

AF:

0.0429

Gnomad AMR exome

AF:

0.00263

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000185

Gnomad OTH exome

AF:

0.00277

GnomAD4 exome

AF:

0.00128

AC:

1870

AN:

1461780

Hom.:

Cov.:

AF XY:

0.00109

AC XY:

791

AN XY:

727190

show subpopulations

Gnomad4 AFR exome

AF:

0.0415

Gnomad4 AMR exome

AF:

0.00318

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000139

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000133

Gnomad4 OTH exome

AF:

0.00283

GnomAD4 genome

AF:

0.0126

AC:

1921

AN:

152292

Hom.:

Cov.:

AF XY:

0.0120

AC XY:

894

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.0419

Gnomad4 AMR

AF:

0.00967

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00804

Alfa

AF:

0.00338

Hom.:

Bravo

AF:

0.0145

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0399

AC:

176

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.00394

AC:

479

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000415

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hyperprolinemia type 2

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 23, 2024	- -
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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

0.090

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.42

T;.;T;.

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.99

.;D;D;D

MetaRNN

Benign

0.0097

T;T;T;T

MetaSVM

Benign

-0.55

MutationAssessor

Pathogenic

3.0

M;.;M;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-6.6

D;D;D;D

REVEL

Uncertain

0.44

Sift

Uncertain

0.014

D;D;D;T

Sift4G

Uncertain

0.055

T;T;T;T

Polyphen

0.89

P;.;P;.

Vest4

0.84

MVP

0.92

MPC

0.52

ClinPred

0.12

GERP RS

4.8

Varity_R

0.58

gMVP

0.74

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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