1-18871672-G-A

Position:

• chr1-18871672-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_003748.4(ALDH4A1):​c.*1173C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00636 in 152,344 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0064 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ALDH4A1 NM_003748.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.649

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00636 (969/152344) while in subpopulation NFE AF= 0.00722 (491/68042). AF 95% confidence interval is 0.00669. There are 2 homozygotes in gnomad4. There are 512 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALDH4A1	NM_003748.4	c.*1173C>T		3_prime_UTR_variant	15/15	ENST00000375341.8
ALDH4A1	NM_001161504.2	c.*1173C>T		3_prime_UTR_variant	15/15
ALDH4A1	NM_001319218.2	c.*1173C>T		3_prime_UTR_variant	14/14
ALDH4A1	NM_170726.3	c.*160C>T		3_prime_UTR_variant	16/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH4A1	ENST00000375341.8	c.*1173C>T		3_prime_UTR_variant	15/15	1	NM_003748.4	P1
ALDH4A1	ENST00000290597.9	c.*160C>T		3_prime_UTR_variant	16/16	1		P1
ALDH4A1	ENST00000538839.5	c.*1173C>T		3_prime_UTR_variant	14/14	1

Frequencies

GnomAD3 genomes AF: 0.00637 AC: 970 AN: 152226 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.0216

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.0259

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00722

Gnomad OTH AF: 0.00669

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 180 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 126

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00636 AC: 969 AN: 152344 Hom.: 2 Cov.: 33 AF XY: 0.00687 AC XY: 512 AN XY: 74508

Gnomad4 AFR AF: 0.00135

Gnomad4 AMR AF: 0.00314

Gnomad4 ASJ AF: 0.0216

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.0259

Gnomad4 NFE AF: 0.00722

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00682 Hom.: 8

Bravo AF: 0.00482

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hyperprolinemia type 2 Uncertain:1

Uncertain significance, 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, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.5
DANN	Benign	0.38
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs115664776; hg19: chr1-19198166;