1-18877467-C-T

Variant names:

• chr1-18877467-C-T
• rs41310410
• NM_003748.4:c.1086G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_003748.4(ALDH4A1):​c.1086G>A​(p.Pro362Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.031 in 1,594,862 control chromosomes in the GnomAD database, including 865 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. P362P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.024 (68 hom., cov: 32)
  • Exomes 𝑓: 0.032 (797 hom.)
• Consequence: ALDH4A1 NM_003748.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.104
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• hyperprolinemia type 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.26).
• BP6: Variant 1-18877467-C-T is Benign according to our data. Variant chr1-18877467-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 471326.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.104 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0242 (3686/152354) while in subpopulation NFE AF = 0.0336 (2283/68024). AF 95% confidence interval is 0.0324. There are 68 homozygotes in GnomAd4. There are 1819 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 68 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH4A1	NM_003748.4	c.1086G>A	p.Pro362Pro	synonymous_variant	Exon 10 of 15	ENST00000375341.8	NP_003739.2
ALDH4A1	NM_170726.3	c.1086G>A	p.Pro362Pro	synonymous_variant	Exon 10 of 16		NP_733844.1
ALDH4A1	NM_001319218.2	c.1086G>A	p.Pro362Pro	synonymous_variant	Exon 10 of 14		NP_001306147.1
ALDH4A1	NM_001161504.2	c.906G>A	p.Pro302Pro	synonymous_variant	Exon 10 of 15		NP_001154976.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH4A1	ENST00000375341.8	c.1086G>A	p.Pro362Pro	synonymous_variant	Exon 10 of 15	1	NM_003748.4	ENSP00000364490.3
ALDH4A1	ENST00000290597.9	c.1086G>A	p.Pro362Pro	synonymous_variant	Exon 10 of 16	1		ENSP00000290597.5
ALDH4A1	ENST00000538839.5	c.1086G>A	p.Pro362Pro	synonymous_variant	Exon 10 of 14	1		ENSP00000446071.1
ALDH4A1	ENST00000538309.5	c.906G>A	p.Pro302Pro	synonymous_variant	Exon 10 of 15	2		ENSP00000442988.1

Frequencies

GnomAD3 genomes AF: 0.0242 AC: 3684 AN: 152236 Hom.: 68 Cov.: 32

Gnomad AFR AF: 0.00629

Gnomad AMI AF: 0.0822

Gnomad AMR AF: 0.0289

Gnomad ASJ AF: 0.0628

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00496

Gnomad FIN AF: 0.0293

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0336

Gnomad OTH AF: 0.0297

GnomAD2 exomes AF: 0.0248 AC: 5426 AN: 219070 AF XY: 0.0244

Gnomad AFR exome AF: 0.00538

Gnomad AMR exome AF: 0.0167

Gnomad ASJ exome AF: 0.0491

Gnomad EAS exome AF: 0.0000605

Gnomad FIN exome AF: 0.0295

Gnomad NFE exome AF: 0.0360

Gnomad OTH exome AF: 0.0295

GnomAD4 exome AF: 0.0317 AC: 45680 AN: 1442508 Hom.: 797 Cov.: 33 AF XY: 0.0310 AC XY: 22211 AN XY: 715770

African (AFR) AF: 0.00512 AC: 170 AN: 33186

American (AMR) AF: 0.0176 AC: 750 AN: 42538

Ashkenazi Jewish (ASJ) AF: 0.0517 AC: 1331 AN: 25746

East Asian (EAS) AF: 0.00 AC: 0 AN: 38982

South Asian (SAS) AF: 0.00605 AC: 505 AN: 83450

European-Finnish (FIN) AF: 0.0277 AC: 1407 AN: 50822

Middle Eastern (MID) AF: 0.0182 AC: 101 AN: 5544

European-Non Finnish (NFE) AF: 0.0361 AC: 39838 AN: 1102592

Other (OTH) AF: 0.0265 AC: 1578 AN: 59648

GnomAD4 genome AF: 0.0242 AC: 3686 AN: 152354 Hom.: 68 Cov.: 32 AF XY: 0.0244 AC XY: 1819 AN XY: 74496

African (AFR) AF: 0.00627 AC: 261 AN: 41598

American (AMR) AF: 0.0289 AC: 443 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.0628 AC: 218 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00517 AC: 25 AN: 4832

European-Finnish (FIN) AF: 0.0293 AC: 311 AN: 10622

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0336 AC: 2283 AN: 68024

Other (OTH) AF: 0.0294 AC: 62 AN: 2112

Alfa AF: 0.0313 Hom.: 201

Bravo AF: 0.0238

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyperprolinemia type 2 Benign:2

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

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 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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
CADD	Benign	12
DANN	Benign	0.93
PhyloP100		-0.10
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs41310410; hg19: chr1-19203961;