1-18872954-G-T

Variant names:

• chr1-18872954-G-T
• rs61757683
• NM_003748.4:c.1583C>A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP3 BP4_Strong BP6 BS1 BS2

The NM_003748.4(ALDH4A1):​c.1583C>A​(p.Thr528Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0224 in 1,613,640 control chromosomes in the GnomAD database, including 484 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.017 (38 hom., cov: 33)
  • Exomes 𝑓: 0.023 (446 hom.)
• Consequence: ALDH4A1 NM_003748.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 9.74

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 -12 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 6: AlphaMissense, Cadd, Eigen, FATHMM_MKL, MutationAssessor, phyloP100way_vertebrate [when BayesDel_addAF, max_spliceai, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.01019305).
• BP6: Variant 1-18872954-G-T is Benign according to our data. Variant chr1-18872954-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 471329.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}. Variant chr1-18872954-G-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0169 (2571/152308) while in subpopulation NFE AF= 0.0252 (1715/68024). AF 95% confidence interval is 0.0242. There are 38 homozygotes in gnomad4. There are 1267 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 38 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH4A1	NM_003748.4	c.1583C>A	p.Thr528Asn	missense_variant	Exon 15 of 15	ENST00000375341.8	NP_003739.2
ALDH4A1	NM_170726.3	c.1583C>A	p.Thr528Asn	missense_variant	Exon 15 of 16		NP_733844.1
ALDH4A1	NM_001319218.2	c.1430C>A	p.Thr477Asn	missense_variant	Exon 14 of 14		NP_001306147.1
ALDH4A1	NM_001161504.2	c.1403C>A	p.Thr468Asn	missense_variant	Exon 15 of 15		NP_001154976.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH4A1	ENST00000375341.8	c.1583C>A	p.Thr528Asn	missense_variant	Exon 15 of 15	1	NM_003748.4	ENSP00000364490.3
ALDH4A1	ENST00000290597.9	c.1583C>A	p.Thr528Asn	missense_variant	Exon 15 of 16	1		ENSP00000290597.5
ALDH4A1	ENST00000538839.5	c.1430C>A	p.Thr477Asn	missense_variant	Exon 14 of 14	1		ENSP00000446071.1
ALDH4A1	ENST00000538309.5	c.1403C>A	p.Thr468Asn	missense_variant	Exon 15 of 15	2		ENSP00000442988.1

Frequencies

GnomAD3 genomes AF: 0.0169 AC: 2572 AN: 152190 Hom.: 38 Cov.: 33

Gnomad AFR AF: 0.00405

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.00942

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.0426

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0252

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.0168 AC: 4216 AN: 251076 Hom.: 64 AF XY: 0.0169 AC XY: 2296 AN XY: 135730

Gnomad AFR exome AF: 0.00370

Gnomad AMR exome AF: 0.00630

Gnomad ASJ exome AF: 0.0101

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00206

Gnomad FIN exome AF: 0.0393

Gnomad NFE exome AF: 0.0248

Gnomad OTH exome AF: 0.0179

GnomAD4 exome AF: 0.0230 AC: 33593 AN: 1461332 Hom.: 446 Cov.: 31 AF XY: 0.0223 AC XY: 16234 AN XY: 726998

Gnomad4 AFR exome AF: 0.00314

Gnomad4 AMR exome AF: 0.00642

Gnomad4 ASJ exome AF: 0.0107

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00184

Gnomad4 FIN exome AF: 0.0383

Gnomad4 NFE exome AF: 0.0267

Gnomad4 OTH exome AF: 0.0173

GnomAD4 genome AF: 0.0169 AC: 2571 AN: 152308 Hom.: 38 Cov.: 33 AF XY: 0.0170 AC XY: 1267 AN XY: 74476

Gnomad4 AFR AF: 0.00404

Gnomad4 AMR AF: 0.00941

Gnomad4 ASJ AF: 0.0107

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.0426

Gnomad4 NFE AF: 0.0252

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.0211 Hom.: 58

Bravo AF: 0.0140

TwinsUK AF: 0.0254 AC: 94

ALSPAC AF: 0.0280 AC: 108

ESP6500AA AF: 0.00363 AC: 16

ESP6500EA AF: 0.0243 AC: 209

ExAC AF: 0.0167 AC: 2024

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0209

EpiControl AF: 0.0209

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hyperprolinemia type 2 Uncertain:1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.57	D;.;D;.
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;D;D;D
MetaRNN	Benign	0.010	T;T;T;T
MetaSVM	Uncertain	0.35	D
MutationAssessor	Pathogenic	4.2	H;.;H;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-4.0	D;D;D;D
REVEL	Uncertain	0.64
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	D;.;D;.
Vest4		0.76
MPC		0.43
ClinPred		0.057	T
GERP RS		4.8
Varity_R		0.84
gMVP		0.78

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: rs61757683; hg19: chr1-19199448;