chr1-18871570-T-G

Position:

• chr1-18871570-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003748.4(ALDH4A1):​c.*1275A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.242 in 152,262 control chromosomes in the GnomAD database, including 4,711 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (4699 hom., cov: 33)
  • Exomes 𝑓: 0.25 (12 hom.)
• Consequence: ALDH4A1 NM_003748.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.922

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 1-18871570-T-G is Benign according to our data. Variant chr1-18871570-T-G is described in ClinVar as [Benign]. Clinvar id is 294333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.274 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALDH4A1	NM_003748.4	c.*1275A>C		3_prime_UTR_variant	15/15	ENST00000375341.8
ALDH4A1	NM_001161504.2	c.*1275A>C		3_prime_UTR_variant	15/15
ALDH4A1	NM_001319218.2	c.*1275A>C		3_prime_UTR_variant	14/14
ALDH4A1	NM_170726.3	c.*262A>C		3_prime_UTR_variant	16/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH4A1	ENST00000375341.8	c.*1275A>C		3_prime_UTR_variant	15/15	1	NM_003748.4	P1
ALDH4A1	ENST00000290597.9	c.*262A>C		3_prime_UTR_variant	16/16	1		P1
ALDH4A1	ENST00000538839.5	c.*1275A>C		3_prime_UTR_variant	14/14	1

Frequencies

GnomAD3 genomes AF: 0.242 AC: 36757 AN: 151886 Hom.: 4696 Cov.: 33

Gnomad AFR AF: 0.216

Gnomad AMI AF: 0.362

Gnomad AMR AF: 0.234

Gnomad ASJ AF: 0.284

Gnomad EAS AF: 0.0350

Gnomad SAS AF: 0.159

Gnomad FIN AF: 0.244

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.277

Gnomad OTH AF: 0.250

GnomAD4 exome AF: 0.254 AC: 65 AN: 256 Hom.: 12 Cov.: 0 AF XY: 0.250 AC XY: 51 AN XY: 204

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: 0.389

Gnomad4 NFE exome AF: 0.267

Gnomad4 OTH exome AF: 0.250

GnomAD4 genome AF: 0.242 AC: 36782 AN: 152006 Hom.: 4699 Cov.: 33 AF XY: 0.236 AC XY: 17541 AN XY: 74306

Gnomad4 AFR AF: 0.216

Gnomad4 AMR AF: 0.234

Gnomad4 ASJ AF: 0.284

Gnomad4 EAS AF: 0.0350

Gnomad4 SAS AF: 0.159

Gnomad4 FIN AF: 0.244

Gnomad4 NFE AF: 0.277

Gnomad4 OTH AF: 0.251

Alfa AF: 0.275 Hom.: 7393

Bravo AF: 0.243

Asia WGS AF: 0.114 AC: 400 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyperprolinemia type 2 Benign:1

Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	13
DANN	Benign	0.82
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3

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: rs1138333; hg19: chr1-19198064;