chr1-18877231-A-G

Position:

chr1-18877231-A-G

Variant summary

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

The NM_003748.4(ALDH4A1):c.1162T>C(p.Phe388Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0163 in 1,608,354 control chromosomes in the GnomAD database, including 281 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.014 ( 16 hom., cov: 32)

Exomes 𝑓: 0.017 ( 265 hom. )

Consequence

ALDH4A1
NM_003748.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 4.43

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=0.0095697045).

BP6

Variant 1-18877231-A-G is Benign according to our data. Variant chr1-18877231-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 294377.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-18877231-A-G is described in Lovd as [Likely_benign].

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0523 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ALDH4A1	NM_003748.4 linkuse as main transcript	c.1162T>C	p.Phe388Leu	missense_variant	11/15	ENST00000375341.8	NP_003739.2
ALDH4A1	NM_170726.3 linkuse as main transcript	c.1162T>C	p.Phe388Leu	missense_variant	11/16		NP_733844.1
ALDH4A1	NM_001319218.2 linkuse as main transcript	c.1162T>C	p.Phe388Leu	missense_variant	11/14		NP_001306147.1
ALDH4A1	NM_001161504.2 linkuse as main transcript	c.982T>C	p.Phe328Leu	missense_variant	11/15		NP_001154976.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALDH4A1	ENST00000375341.8 linkuse as main transcript	c.1162T>C	p.Phe388Leu	missense_variant	11/15	1	NM_003748.4	ENSP00000364490	P1	P30038-1
ALDH4A1	ENST00000290597.9 linkuse as main transcript	c.1162T>C	p.Phe388Leu	missense_variant	11/16	1		ENSP00000290597	P1	P30038-1
ALDH4A1	ENST00000538839.5 linkuse as main transcript	c.1162T>C	p.Phe388Leu	missense_variant	11/14	1		ENSP00000446071		P30038-3
ALDH4A1	ENST00000538309.5 linkuse as main transcript	c.982T>C	p.Phe328Leu	missense_variant	11/15	2		ENSP00000442988		P30038-2

Frequencies

GnomAD3 genomes

AF:

0.0136

AC:

2064

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00294

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0142

Gnomad ASJ

AF:

0.0360

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.0184

Gnomad FIN

AF:

0.0224

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.0180

Gnomad OTH

AF:

0.0153

GnomAD3 exomes

AF:

0.0164

AC:

3932

AN:

240130

Hom.:

AF XY:

0.0173

AC XY:

2244

AN XY:

129768

show subpopulations

Gnomad AFR exome

AF:

0.00290

Gnomad AMR exome

AF:

0.0129

Gnomad ASJ exome

AF:

0.0257

Gnomad EAS exome

AF:

0.000668

Gnomad SAS exome

AF:

0.0170

Gnomad FIN exome

AF:

0.0247

Gnomad NFE exome

AF:

0.0189

Gnomad OTH exome

AF:

0.0243

GnomAD4 exome

AF:

0.0166

AC:

24156

AN:

1456092

Hom.:

265

Cov.:

AF XY:

0.0169

AC XY:

12212

AN XY:

723694

show subpopulations

Gnomad4 AFR exome

AF:

0.00424

Gnomad4 AMR exome

AF:

0.0127

Gnomad4 ASJ exome

AF:

0.0281

Gnomad4 EAS exome

AF:

0.000305

Gnomad4 SAS exome

AF:

0.0181

Gnomad4 FIN exome

AF:

0.0239

Gnomad4 NFE exome

AF:

0.0166

Gnomad4 OTH exome

AF:

0.0198

GnomAD4 genome

AF:

0.0135

AC:

2062

AN:

152262

Hom.:

Cov.:

AF XY:

0.0137

AC XY:

1018

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.00291

Gnomad4 AMR

AF:

0.0142

Gnomad4 ASJ

AF:

0.0360

Gnomad4 EAS

AF:

0.000387

Gnomad4 SAS

AF:

0.0187

Gnomad4 FIN

AF:

0.0224

Gnomad4 NFE

AF:

0.0180

Gnomad4 OTH

AF:

0.0151

Alfa

AF:

0.0166

Hom.:

Bravo

AF:

0.0125

TwinsUK

AF:

0.0151

AC:

ALSPAC

AF:

0.0171

AC:

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.0164

AC:

141

ExAC

AF:

0.0162

AC:

1961

Asia WGS

AF:

0.00924

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Hyperprolinemia type 2

Benign:2

Likely 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 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	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.60

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.066

T;.;T;.

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.14

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.89

.;D;D;D

MetaRNN

Benign

0.0096

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.23

N;N;N;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.59

PROVEAN

Benign

0.84

N;N;N;N

REVEL

Benign

0.14

Sift

Benign

0.35

T;T;T;T

Sift4G

Benign

0.44

T;T;T;T

Polyphen

0.0010

B;.;B;.

Vest4

0.35

MutPred

0.48

Loss of catalytic residue at F388 (P = 0.1151);Loss of catalytic residue at F388 (P = 0.1151);Loss of catalytic residue at F388 (P = 0.1151);.;

MPC

0.12

ClinPred

0.013

GERP RS

3.1

Varity_R

0.20

gMVP

0.79

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