rs75705742

Positions:

• chr1-18897145-G-A
• chr1-18897145-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_003748.4(ALDH4A1):​c.62+5317C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00489 in 505,514 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.012 (30 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (9 hom.)
• Consequence: ALDH4A1 NM_003748.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.59

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]

MIR1290 (HGNC:35283): (microRNA 1290) 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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0124 (1887/152308) while in subpopulation AFR AF= 0.0426 (1772/41560). AF 95% confidence interval is 0.041. There are 30 homozygotes in gnomad4. There are 923 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 30 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALDH4A1	NM_003748.4	c.62+5317C>T		intron_variant		ENST00000375341.8
MIR1290	NR_031622.1	n.4C>T		non_coding_transcript_exon_variant	1/1
ALDH4A1	NM_001319218.2	c.62+5317C>T		intron_variant
ALDH4A1	NM_170726.3	c.62+5317C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH4A1	ENST00000375341.8	c.62+5317C>T		intron_variant		1	NM_003748.4	P1
MIR1290	ENST00000408735.1	n.4C>T		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.0124 AC: 1888 AN: 152190 Hom.: 30 Cov.: 32

Gnomad AFR AF: 0.0428

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00517

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.00958

GnomAD3 exomes AF: 0.00332 AC: 638 AN: 192218 Hom.: 16 AF XY: 0.00253 AC XY: 264 AN XY: 104204

Gnomad AFR exome AF: 0.0475

Gnomad AMR exome AF: 0.00237

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000192

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000286

Gnomad OTH exome AF: 0.00235

GnomAD4 exome AF: 0.00165 AC: 584 AN: 353206 Hom.: 9 Cov.: 0 AF XY: 0.00127 AC XY: 255 AN XY: 200848

Gnomad4 AFR exome AF: 0.0442

Gnomad4 AMR exome AF: 0.00221

Gnomad4 ASJ exome AF: 0.0000891

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000110

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000175

Gnomad4 OTH exome AF: 0.00254

GnomAD4 genome AF: 0.0124 AC: 1887 AN: 152308 Hom.: 30 Cov.: 32 AF XY: 0.0124 AC XY: 923 AN XY: 74476

Gnomad4 AFR AF: 0.0426

Gnomad4 AMR AF: 0.00516

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000220

Gnomad4 OTH AF: 0.00948

Alfa AF: 0.00484 Hom.: 7

Bravo AF: 0.0145

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	2.3
DANN	Benign	0.73

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: rs75705742; hg19: chr1-19223639;