1-18885513-G-A

Position:

• chr1-18885513-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_003748.4(ALDH4A1):​c.413C>T​(p.Pro138Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0024 in 1,542,014 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P138P) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0024 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0024 (4 hom.)
• Consequence: ALDH4A1 NM_003748.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 6.21

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009564936).
• BP6: Variant 1-18885513-G-A is Benign according to our data. Variant chr1-18885513-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 294391.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=1}. Variant chr1-18885513-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00237 (347/146580) while in subpopulation AFR AF= 0.004 (160/40034). AF 95% confidence interval is 0.00349. There are 1 homozygotes in gnomad4. There are 151 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALDH4A1	NM_003748.4	c.413C>T	p.Pro138Leu	missense_variant	5/15	ENST00000375341.8
ALDH4A1	NM_170726.3	c.413C>T	p.Pro138Leu	missense_variant	5/16
ALDH4A1	NM_001319218.2	c.413C>T	p.Pro138Leu	missense_variant	5/14
ALDH4A1	NM_001161504.2	c.233C>T	p.Pro78Leu	missense_variant	5/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH4A1	ENST00000375341.8	c.413C>T	p.Pro138Leu	missense_variant	5/15	1	NM_003748.4	P1

Frequencies

GnomAD3 genomes AF: 0.00237 AC: 347 AN: 146464 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00398

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000415

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000228

Gnomad FIN AF: 0.000624

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00258

Gnomad OTH AF: 0.00147

GnomAD3 exomes AF: 0.00128 AC: 286 AN: 223664 Hom.: 0 AF XY: 0.00119 AC XY: 144 AN XY: 121166

Gnomad AFR exome AF: 0.00272

Gnomad AMR exome AF: 0.000217

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000716

Gnomad FIN exome AF: 0.000913

Gnomad NFE exome AF: 0.00214

Gnomad OTH exome AF: 0.00177

GnomAD4 exome AF: 0.00241 AC: 3359 AN: 1395434 Hom.: 4 Cov.: 37 AF XY: 0.00236 AC XY: 1637 AN XY: 692414

Gnomad4 AFR exome AF: 0.00285

Gnomad4 AMR exome AF: 0.000293

Gnomad4 ASJ exome AF: 0.0000418

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000360

Gnomad4 FIN exome AF: 0.00156

Gnomad4 NFE exome AF: 0.00290

Gnomad4 OTH exome AF: 0.00128

GnomAD4 genome AF: 0.00237 AC: 347 AN: 146580 Hom.: 1 Cov.: 31 AF XY: 0.00212 AC XY: 151 AN XY: 71220

Gnomad4 AFR AF: 0.00400

Gnomad4 AMR AF: 0.000415

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000228

Gnomad4 FIN AF: 0.000624

Gnomad4 NFE AF: 0.00256

Gnomad4 OTH AF: 0.00146

Alfa AF: 0.00170 Hom.: 2

Bravo AF: 0.00223

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.00142 AC: 172

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hyperprolinemia type 2 Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 17, 2024	- -
Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Intellectual disability Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2022

ALDH4A1: BP4 -

ALDH4A1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 01, 2022

This variant is classified as likely 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	0.15
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.38	T;.;T;.;.
Eigen	Benign	0.14
Eigen_PC	Benign	0.053
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	.;D;D;D;D
MetaRNN	Benign	0.0096	T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.9	M;M;M;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.7	D;D;D;D;D
REVEL	Benign	0.16
Sift	Uncertain	0.0050	D;D;D;D;D
Sift4G	Uncertain	0.011	D;T;D;T;.
Polyphen		0.96	D;.;D;.;.
Vest4		0.57
MVP		0.54
MPC		0.11
ClinPred		0.10	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.25
gMVP		0.57

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

Other links and lift over

dbSNP: rs139640415; hg19: chr1-19212007; COSMIC: COSV99311564; COSMIC: COSV99311564;