rs6426813

Positions:

• chr1-18877660-G-A
• chr1-18877660-G-T

Variant summary

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

The ENST00000375341.8(ALDH4A1):​c.941-48C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.734 in 1,384,948 control chromosomes in the GnomAD database, including 376,492 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.72 (40377 hom., cov: 33)
  • Exomes 𝑓: 0.74 (336115 hom.)
• Consequence: ALDH4A1 ENST00000375341.8 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.839

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=-0.91).
• BP6: Variant 1-18877660-G-A is Benign according to our data. Variant chr1-18877660-G-A is described in ClinVar as [Benign]. Clinvar id is 1188873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.933 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALDH4A1	NM_003748.4	c.941-48C>T		intron_variant		ENST00000375341.8	NP_003739.2
ALDH4A1	NM_001161504.2	c.761-48C>T		intron_variant			NP_001154976.1
ALDH4A1	NM_001319218.2	c.941-48C>T		intron_variant			NP_001306147.1
ALDH4A1	NM_170726.3	c.941-48C>T		intron_variant			NP_733844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALDH4A1	ENST00000375341.8	c.941-48C>T		intron_variant		1	NM_003748.4	ENSP00000364490	P1
ALDH4A1	ENST00000290597.9	c.941-48C>T		intron_variant		1		ENSP00000290597	P1
ALDH4A1	ENST00000538839.5	c.941-48C>T		intron_variant		1		ENSP00000446071
ALDH4A1	ENST00000538309.5	c.761-48C>T		intron_variant		2		ENSP00000442988

Frequencies

GnomAD3 genomes AF: 0.724 AC: 110064 AN: 151962 Hom.: 40352 Cov.: 33

Gnomad AFR AF: 0.700

Gnomad AMI AF: 0.849

Gnomad AMR AF: 0.823

Gnomad ASJ AF: 0.804

Gnomad EAS AF: 0.956

Gnomad SAS AF: 0.856

Gnomad FIN AF: 0.619

Gnomad MID AF: 0.861

Gnomad NFE AF: 0.699

Gnomad OTH AF: 0.749

GnomAD3 exomes AF: 0.770 AC: 165590 AN: 215114 Hom.: 64530 AF XY: 0.767 AC XY: 91021 AN XY: 118632

Gnomad AFR exome AF: 0.696

Gnomad AMR exome AF: 0.886

Gnomad ASJ exome AF: 0.810

Gnomad EAS exome AF: 0.954

Gnomad SAS exome AF: 0.841

Gnomad FIN exome AF: 0.636

Gnomad NFE exome AF: 0.707

Gnomad OTH exome AF: 0.779

GnomAD4 exome AF: 0.735 AC: 906548 AN: 1232868 Hom.: 336115 Cov.: 25 AF XY: 0.738 AC XY: 457695 AN XY: 620536

Gnomad4 AFR exome AF: 0.701

Gnomad4 AMR exome AF: 0.879

Gnomad4 ASJ exome AF: 0.806

Gnomad4 EAS exome AF: 0.955

Gnomad4 SAS exome AF: 0.838

Gnomad4 FIN exome AF: 0.634

Gnomad4 NFE exome AF: 0.714

Gnomad4 OTH exome AF: 0.748

GnomAD4 genome AF: 0.724 AC: 110145 AN: 152080 Hom.: 40377 Cov.: 33 AF XY: 0.726 AC XY: 53997 AN XY: 74346

Gnomad4 AFR AF: 0.700

Gnomad4 AMR AF: 0.824

Gnomad4 ASJ AF: 0.804

Gnomad4 EAS AF: 0.955

Gnomad4 SAS AF: 0.855

Gnomad4 FIN AF: 0.619

Gnomad4 NFE AF: 0.699

Gnomad4 OTH AF: 0.746

Alfa AF: 0.690 Hom.: 6982

Bravo AF: 0.739

Asia WGS AF: 0.886 AC: 3079 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

Genome-Nilou Lab

Jul 14, 2021

- -

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	-0.91
CADD	Benign	1.4
DANN	Benign	0.79
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs6426813; hg19: chr1-19204154;