1-18872143-G-A

Position:

• chr1-18872143-G-A

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.*702C>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 0.399 in 152,480 control chromosomes in the GnomAD database, including 13,063 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (13025 hom., cov: 34)
  • Exomes 𝑓: 0.44 (38 hom.)
• Consequence: ALDH4A1 NM_003748.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.292

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=-0.81).
• BP6: Variant 1-18872143-G-A is Benign according to our data. Variant chr1-18872143-G-A is described in ClinVar as [Benign]. Clinvar id is 294347.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.661 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALDH4A1	NM_003748.4	c.*702C>T		3_prime_UTR_variant	15/15	ENST00000375341.8
ALDH4A1	NM_001161504.2	c.*702C>T		3_prime_UTR_variant	15/15
ALDH4A1	NM_001319218.2	c.*702C>T		3_prime_UTR_variant	14/14
ALDH4A1	NM_170726.3	c.*42-353C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH4A1	ENST00000375341.8	c.*702C>T		3_prime_UTR_variant	15/15	1	NM_003748.4	P1
ALDH4A1	ENST00000538839.5	c.*702C>T		3_prime_UTR_variant	14/14	1
ALDH4A1	ENST00000290597.9	c.*42-353C>T		intron_variant		1		P1

Frequencies

GnomAD3 genomes AF: 0.398 AC: 60591 AN: 152070 Hom.: 13009 Cov.: 34

Gnomad AFR AF: 0.244

Gnomad AMI AF: 0.425

Gnomad AMR AF: 0.521

Gnomad ASJ AF: 0.409

Gnomad EAS AF: 0.680

Gnomad SAS AF: 0.596

Gnomad FIN AF: 0.417

Gnomad MID AF: 0.402

Gnomad NFE AF: 0.425

Gnomad OTH AF: 0.420

GnomAD4 exome AF: 0.438 AC: 128 AN: 292 Hom.: 38 Cov.: 0 AF XY: 0.478 AC XY: 110 AN XY: 230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 1.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.600

Gnomad4 SAS exome AF: 1.00

Gnomad4 FIN exome AF: 0.333

Gnomad4 NFE exome AF: 0.440

Gnomad4 OTH exome AF: 0.357

GnomAD4 genome AF: 0.398 AC: 60639 AN: 152188 Hom.: 13025 Cov.: 34 AF XY: 0.408 AC XY: 30325 AN XY: 74406

Gnomad4 AFR AF: 0.244

Gnomad4 AMR AF: 0.522

Gnomad4 ASJ AF: 0.409

Gnomad4 EAS AF: 0.680

Gnomad4 SAS AF: 0.596

Gnomad4 FIN AF: 0.417

Gnomad4 NFE AF: 0.425

Gnomad4 OTH AF: 0.420

Alfa AF: 0.429 Hom.: 14502

Bravo AF: 0.398

Asia WGS AF: 0.597 AC: 2076 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	-0.81
CADD	Benign	5.2
DANN	Benign	0.79
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: rs3202002; hg19: chr1-19198637;