rs61749348

Positions:

• chr1-18874494-G-A
• chr1-18874494-G-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_003748.4(ALDH4A1):​c.1548C>T​(p.Gly516Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0268 in 1,614,068 control chromosomes in the GnomAD database, including 1,434 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.060 (567 hom., cov: 34)
  • Exomes 𝑓: 0.023 (867 hom.)
• Consequence: ALDH4A1 NM_003748.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.11

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 -16 ACMG points.

• BP6: Variant 1-18874494-G-A is Benign according to our data. Variant chr1-18874494-G-A is described in ClinVar as [Benign]. Clinvar id is 294365.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.156 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALDH4A1	NM_003748.4	c.1548C>T	p.Gly516Gly	synonymous_variant	14/15	ENST00000375341.8	NP_003739.2
ALDH4A1	NM_170726.3	c.1548C>T	p.Gly516Gly	synonymous_variant	14/16		NP_733844.1
ALDH4A1	NM_001319218.2	c.1395C>T	p.Gly465Gly	synonymous_variant	13/14		NP_001306147.1
ALDH4A1	NM_001161504.2	c.1368C>T	p.Gly456Gly	synonymous_variant	14/15		NP_001154976.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALDH4A1	ENST00000375341.8	c.1548C>T	p.Gly516Gly	synonymous_variant	14/15	1	NM_003748.4	ENSP00000364490.3
ALDH4A1	ENST00000290597.9	c.1548C>T	p.Gly516Gly	synonymous_variant	14/16	1		ENSP00000290597.5
ALDH4A1	ENST00000538839.5	c.1395C>T	p.Gly465Gly	synonymous_variant	13/14	1		ENSP00000446071.1
ALDH4A1	ENST00000538309.5	c.1368C>T	p.Gly456Gly	synonymous_variant	14/15	2		ENSP00000442988.1

Frequencies

GnomAD3 genomes AF: 0.0603 AC: 9168 AN: 152156 Hom.: 565 Cov.: 34

Gnomad AFR AF: 0.159

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0352

Gnomad ASJ AF: 0.0397

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0188

Gnomad FIN AF: 0.0235

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0210

Gnomad OTH AF: 0.0498

GnomAD3 exomes AF: 0.0298 AC: 7481 AN: 250986 Hom.: 301 AF XY: 0.0276 AC XY: 3742 AN XY: 135664

Gnomad AFR exome AF: 0.164

Gnomad AMR exome AF: 0.0202

Gnomad ASJ exome AF: 0.0295

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0163

Gnomad FIN exome AF: 0.0271

Gnomad NFE exome AF: 0.0223

Gnomad OTH exome AF: 0.0336

GnomAD4 exome AF: 0.0233 AC: 34085 AN: 1461794 Hom.: 867 Cov.: 32 AF XY: 0.0228 AC XY: 16615 AN XY: 727192

Gnomad4 AFR exome AF: 0.165

Gnomad4 AMR exome AF: 0.0215

Gnomad4 ASJ exome AF: 0.0315

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0172

Gnomad4 FIN exome AF: 0.0268

Gnomad4 NFE exome AF: 0.0194

Gnomad4 OTH exome AF: 0.0315

GnomAD4 genome AF: 0.0603 AC: 9185 AN: 152274 Hom.: 567 Cov.: 34 AF XY: 0.0582 AC XY: 4333 AN XY: 74450

Gnomad4 AFR AF: 0.159

Gnomad4 AMR AF: 0.0351

Gnomad4 ASJ AF: 0.0397

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0188

Gnomad4 FIN AF: 0.0235

Gnomad4 NFE AF: 0.0209

Gnomad4 OTH AF: 0.0493

Alfa AF: 0.0325 Hom.: 207

Bravo AF: 0.0659

Asia WGS AF: 0.0200 AC: 72 AN: 3478

EpiCase AF: 0.0264

EpiControl AF: 0.0253

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyperprolinemia type 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
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 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	-0.38
CADD	Benign	17
DANN	Benign	0.89
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.40		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.40		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs61749348; hg19: chr1-19200988;