1-18871606-C-G

Variant names:

• chr1-18871606-C-G
• rs1138328
• NM_003748.4:c.*1239G>C

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.*1239G>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 0.235 in 152,310 control chromosomes in the GnomAD database, including 4,492 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4487 hom., cov: 33)
  • Exomes 𝑓: 0.25 (5 hom.)
• Consequence: ALDH4A1 NM_003748.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.122

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=-0.89).
• BP6: Variant 1-18871606-C-G is Benign according to our data. Variant chr1-18871606-C-G is described in ClinVar as [Benign]. Clinvar id is 294334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.27 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH4A1	NM_003748.4	c.*1239G>C		3_prime_UTR_variant	Exon 15 of 15	ENST00000375341.8	NP_003739.2
ALDH4A1	NM_170726.3	c.*226G>C		3_prime_UTR_variant	Exon 16 of 16		NP_733844.1
ALDH4A1	NM_001319218.2	c.*1239G>C		3_prime_UTR_variant	Exon 14 of 14		NP_001306147.1
ALDH4A1	NM_001161504.2	c.*1239G>C		3_prime_UTR_variant	Exon 15 of 15		NP_001154976.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH4A1	ENST00000375341	c.*1239G>C		3_prime_UTR_variant	Exon 15 of 15	1	NM_003748.4	ENSP00000364490.3
ALDH4A1	ENST00000290597	c.*226G>C		3_prime_UTR_variant	Exon 16 of 16	1		ENSP00000290597.5
ALDH4A1	ENST00000538839	c.*1239G>C		3_prime_UTR_variant	Exon 14 of 14	1		ENSP00000446071.1

Frequencies

GnomAD3 genomes AF: 0.235 AC: 35720 AN: 152060 Hom.: 4485 Cov.: 33

Gnomad AFR AF: 0.209

Gnomad AMI AF: 0.359

Gnomad AMR AF: 0.229

Gnomad ASJ AF: 0.279

Gnomad EAS AF: 0.00193

Gnomad SAS AF: 0.127

Gnomad FIN AF: 0.237

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.273

Gnomad OTH AF: 0.245

GnomAD4 exome AF: 0.250 AC: 33 AN: 132 Hom.: 5 Cov.: 0 AF XY: 0.213 AC XY: 23 AN XY: 108

Gnomad4 AFR exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.200

Gnomad4 NFE exome AF: 0.286

Gnomad4 OTH exome AF: 0.214

GnomAD4 genome AF: 0.235 AC: 35729 AN: 152178 Hom.: 4487 Cov.: 33 AF XY: 0.228 AC XY: 16963 AN XY: 74396

Gnomad4 AFR AF: 0.209

Gnomad4 AMR AF: 0.229

Gnomad4 ASJ AF: 0.279

Gnomad4 EAS AF: 0.00193

Gnomad4 SAS AF: 0.127

Gnomad4 FIN AF: 0.237

Gnomad4 NFE AF: 0.273

Gnomad4 OTH AF: 0.241

Alfa AF: 0.243 Hom.: 589

Bravo AF: 0.237

Asia WGS AF: 0.0730 AC: 259 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyperprolinemia type 2 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: 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 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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: 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	-0.89
CADD	Benign	5.8
DANN	Benign	0.42
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: rs1138328; hg19: chr1-19198100; COSMIC: COSV51895732; COSMIC: COSV51895732;