NM_003748.4:c.62+5317C>T

Variant names:

• chr1-18897145-G-A
• rs75705742
• NM_003748.4:c.62+5317C>T

Variant summary

Our verdict is Benign. The variant received -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
• 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]

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

Our verdict: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 30 AR gene

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.62+5317C>T		intron	N/A	NP_003739.2
	ALDH4A1	NM_170726.3		c.62+5317C>T		intron	N/A	NP_733844.1
	ALDH4A1	NM_001319218.2		c.62+5317C>T		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.62+5317C>T		intron	N/A	ENSP00000364490.3
	ALDH4A1	ENST00000290597.9	TSL:1	c.62+5317C>T		intron	N/A	ENSP00000290597.5
	ALDH4A1	ENST00000538839.5	TSL:1	c.62+5317C>T		intron	N/A	ENSP00000446071.1

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

GnomAD2 exomes AF: 0.00332 AC: 638 AN: 192218 AF XY: 0.00253

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 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

African (AFR) AF: 0.0442 AC: 427 AN: 9656

American (AMR) AF: 0.00221 AC: 69 AN: 31202

Ashkenazi Jewish (ASJ) AF: 0.0000891 AC: 1 AN: 11224

East Asian (EAS) AF: 0.00 AC: 0 AN: 11556

South Asian (SAS) AF: 0.000110 AC: 7 AN: 63454

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30500

Middle Eastern (MID) AF: 0.00397 AC: 9 AN: 2266

European-Non Finnish (NFE) AF: 0.000175 AC: 31 AN: 177618

Other (OTH) AF: 0.00254 AC: 40 AN: 15730

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

African (AFR) AF: 0.0426 AC: 1772 AN: 41560

American (AMR) AF: 0.00516 AC: 79 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000220 AC: 15 AN: 68028

Other (OTH) AF: 0.00948 AC: 20 AN: 2110

Alfa AF: 0.00515 Hom.: 7

Bravo AF: 0.0145

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	2.3
DANN	Benign	0.73
PhyloP100		-1.6
Mutation Taster		=100/0	polymorphism

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: rs75705742; hg19: chr1-19223639;