1-18889340-T-C

Variant names:

• chr1-18889340-T-C
• rs941495
• NM_003748.4:c.249+22A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003748.4(ALDH4A1):​c.249+22A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.961 in 1,549,528 control chromosomes in the GnomAD database, including 716,232 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.97 (71521 hom., cov: 32)
  • Exomes 𝑓: 0.96 (644711 hom.)
• Consequence: ALDH4A1 NM_003748.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.521
• Publications: 6 publications found

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]

ALDH4A1 Gene-Disease associations (from GenCC):

• hyperprolinemia type 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 1-18889340-T-C is Benign according to our data. Variant chr1-18889340-T-C is described in ClinVar as Benign. ClinVar VariationId is 1188912.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.985 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003748.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH4A1	NM_003748.4	MANE Select	c.249+22A>G		intron	N/A	NP_003739.2
	ALDH4A1	NM_170726.3		c.249+22A>G		intron	N/A	NP_733844.1
	ALDH4A1	NM_001319218.2		c.249+22A>G		intron	N/A	NP_001306147.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH4A1	ENST00000375341.8	TSL:1 MANE Select	c.249+22A>G		intron	N/A	ENSP00000364490.3
	ALDH4A1	ENST00000290597.9	TSL:1	c.249+22A>G		intron	N/A	ENSP00000290597.5
	ALDH4A1	ENST00000538839.5	TSL:1	c.249+22A>G		intron	N/A	ENSP00000446071.1

Frequencies

GnomAD3 genomes AF: 0.969 AC: 147473 AN: 152202 Hom.: 71460 Cov.: 32

Gnomad AFR AF: 0.993

Gnomad AMI AF: 0.912

Gnomad AMR AF: 0.971

Gnomad ASJ AF: 0.960

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.991

Gnomad FIN AF: 0.952

Gnomad MID AF: 0.949

Gnomad NFE AF: 0.954

Gnomad OTH AF: 0.966

GnomAD2 exomes AF: 0.968 AC: 151510 AN: 156562 AF XY: 0.969

Gnomad AFR exome AF: 0.993

Gnomad AMR exome AF: 0.973

Gnomad ASJ exome AF: 0.961

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.943

Gnomad NFE exome AF: 0.957

Gnomad OTH exome AF: 0.959

GnomAD4 exome AF: 0.961 AC: 1342054 AN: 1397208 Hom.: 644711 Cov.: 31 AF XY: 0.961 AC XY: 662730 AN XY: 689294

African (AFR) AF: 0.993 AC: 31348 AN: 31558

American (AMR) AF: 0.973 AC: 34721 AN: 35698

Ashkenazi Jewish (ASJ) AF: 0.958 AC: 24107 AN: 25158

East Asian (EAS) AF: 1.00 AC: 35715 AN: 35716

South Asian (SAS) AF: 0.987 AC: 78213 AN: 79208

European-Finnish (FIN) AF: 0.947 AC: 46662 AN: 49248

Middle Eastern (MID) AF: 0.955 AC: 5438 AN: 5696

European-Non Finnish (NFE) AF: 0.956 AC: 1029936 AN: 1076990

Other (OTH) AF: 0.965 AC: 55914 AN: 57936

GnomAD4 genome AF: 0.969 AC: 147593 AN: 152320 Hom.: 71521 Cov.: 32 AF XY: 0.970 AC XY: 72235 AN XY: 74474

African (AFR) AF: 0.993 AC: 41259 AN: 41564

American (AMR) AF: 0.971 AC: 14851 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.960 AC: 3333 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5178 AN: 5180

South Asian (SAS) AF: 0.991 AC: 4781 AN: 4826

European-Finnish (FIN) AF: 0.952 AC: 10112 AN: 10622

Middle Eastern (MID) AF: 0.952 AC: 280 AN: 294

European-Non Finnish (NFE) AF: 0.954 AC: 64927 AN: 68036

Other (OTH) AF: 0.966 AC: 2040 AN: 2112

Alfa AF: 0.960 Hom.: 12979

Bravo AF: 0.971

Asia WGS AF: 0.994 AC: 3454 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyperprolinemia type 2 Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	3.3
DANN	Benign	0.69
PhyloP100		-0.52
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs941495; hg19: chr1-19215834;