1-18883049-A-G

Variant names:

• chr1-18883049-A-G
• rs6426611
• NM_003748.4:c.678+75T>C

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.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
• Publications: 4 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]

MIR4695 (HGNC:41573): (microRNA 4695) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
ALDH4A1	NM_003748.4	c.678+75T>C		intron_variant	Intron 7 of 14	ENST00000375341.8	NP_003739.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH4A1	ENST00000375341.8	c.678+75T>C		intron_variant	Intron 7 of 14	1	NM_003748.4	ENSP00000364490.3

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

African (AFR) AF: 0.893 AC: 29460 AN: 32990

American (AMR) AF: 0.994 AC: 44402 AN: 44648

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 26031 AN: 26032

East Asian (EAS) AF: 1.00 AC: 39566 AN: 39566

South Asian (SAS) AF: 1.00 AC: 85776 AN: 85796

European-Finnish (FIN) AF: 1.00 AC: 52039 AN: 52040

Middle Eastern (MID) AF: 0.995 AC: 5621 AN: 5652

European-Non Finnish (NFE) AF: 1.00 AC: 1094340 AN: 1094586

Other (OTH) AF: 0.993 AC: 59159 AN: 59578

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

African (AFR) AF: 0.896 AC: 37247 AN: 41576

American (AMR) AF: 0.990 AC: 15153 AN: 15312

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5175 AN: 5176

South Asian (SAS) AF: 0.999 AC: 4821 AN: 4824

European-Finnish (FIN) AF: 1.00 AC: 10630 AN: 10630

Middle Eastern (MID) AF: 0.993 AC: 292 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 68012 AN: 68040

Other (OTH) AF: 0.977 AC: 2065 AN: 2114

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

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.0020
DANN	Benign	0.25
PhyloP100		-1.9
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6426611; hg19: chr1-19209543;