1-18877467-C-T

Position:

• chr1-18877467-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_003748.4(ALDH4A1):​c.1086G>A​(p.Pro362=) 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:2
• Conservation: PhyloP100: -0.104

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 -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 [Likely_benign]. Clinvar id is 471326.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-18877467-C-T is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 68 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALDH4A1	NM_003748.4	c.1086G>A	p.Pro362=	synonymous_variant	10/15	ENST00000375341.8
ALDH4A1	NM_170726.3	c.1086G>A	p.Pro362=	synonymous_variant	10/16
ALDH4A1	NM_001319218.2	c.1086G>A	p.Pro362=	synonymous_variant	10/14
ALDH4A1	NM_001161504.2	c.906G>A	p.Pro302=	synonymous_variant	10/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH4A1	ENST00000375341.8	c.1086G>A	p.Pro362=	synonymous_variant	10/15	1	NM_003748.4	P1
ALDH4A1	ENST00000290597.9	c.1086G>A	p.Pro362=	synonymous_variant	10/16	1		P1
ALDH4A1	ENST00000538839.5	c.1086G>A	p.Pro362=	synonymous_variant	10/14	1
ALDH4A1	ENST00000538309.5	c.906G>A	p.Pro302=	synonymous_variant	10/15	2

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

GnomAD3 exomes AF: 0.0248 AC: 5426 AN: 219070 Hom.: 91 AF XY: 0.0244 AC XY: 2886 AN XY: 118378

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 SAS exome AF: 0.00618

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

Gnomad4 AFR exome AF: 0.00512

Gnomad4 AMR exome AF: 0.0176

Gnomad4 ASJ exome AF: 0.0517

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00605

Gnomad4 FIN exome AF: 0.0277

Gnomad4 NFE exome AF: 0.0361

Gnomad4 OTH exome AF: 0.0265

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

Gnomad4 AFR AF: 0.00627

Gnomad4 AMR AF: 0.0289

Gnomad4 ASJ AF: 0.0628

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00517

Gnomad4 FIN AF: 0.0293

Gnomad4 NFE AF: 0.0336

Gnomad4 OTH AF: 0.0294

Alfa AF: 0.0306 Hom.: 91

Bravo AF: 0.0238

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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	Invitae	Jan 29, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
CADD	Benign	12
DANN	Benign	0.93
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs41310410; hg19: chr1-19203961;