rs6426611

Positions:

• chr1-18883049-A-G
• chr1-18883049-A-T

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.678+75T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.994 in 1,593,238 control chromosomes in the GnomAD database, including 787,985 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.97 (71835 hom., cov: 34)
  • Exomes 𝑓: 1.0 (716150 hom.)
• Consequence: ALDH4A1 NM_003748.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.87

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=-0.98).
• BP6: Variant 1-18883049-A-G is Benign according to our data. Variant chr1-18883049-A-G is described in ClinVar as [Benign]. Clinvar id is 1188911.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALDH4A1	NM_003748.4	c.678+75T>C		intron_variant		ENST00000375341.8	NP_003739.2
ALDH4A1	NM_001161504.2	c.498+75T>C		intron_variant			NP_001154976.1
ALDH4A1	NM_001319218.2	c.678+75T>C		intron_variant			NP_001306147.1
ALDH4A1	NM_170726.3	c.678+75T>C		intron_variant			NP_733844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALDH4A1	ENST00000375341.8	c.678+75T>C		intron_variant		1	NM_003748.4	ENSP00000364490	P1

Frequencies

GnomAD3 genomes AF: 0.970 AC: 147693 AN: 152232 Hom.: 71804 Cov.: 34

Gnomad AFR AF: 0.896

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.990

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.999

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.994

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.977

GnomAD4 exome AF: 0.997 AC: 1436394 AN: 1440888 Hom.: 716150 AF XY: 0.997 AC XY: 716173 AN XY: 718102

Gnomad4 AFR exome AF: 0.893

Gnomad4 AMR exome AF: 0.994

Gnomad4 ASJ exome AF: 1.00

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 1.00

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 1.00

Gnomad4 OTH exome AF: 0.993

GnomAD4 genome AF: 0.970 AC: 147779 AN: 152350 Hom.: 71835 Cov.: 34 AF XY: 0.970 AC XY: 72283 AN XY: 74486

Gnomad4 AFR AF: 0.896

Gnomad4 AMR AF: 0.990

Gnomad4 ASJ AF: 1.00

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.999

Gnomad4 FIN AF: 1.00

Gnomad4 NFE AF: 1.00

Gnomad4 OTH AF: 0.977

Alfa AF: 0.981 Hom.: 9122

Bravo AF: 0.965

Asia WGS AF: 0.992 AC: 3452 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	-0.98
CADD	Benign	0.0020
DANN	Benign	0.25

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: rs6426611; hg19: chr1-19209543;