rs28497538

Positions:

• chr1-18879178-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003748.4(ALDH4A1):​c.940+122A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.395 in 947,762 control chromosomes in the GnomAD database, including 76,105 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 0.43 (14332 hom., cov: 32)
  • Exomes 𝑓: 0.39 (61773 hom.)
• Consequence: ALDH4A1 NM_003748.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.63

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.483 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALDH4A1	NM_003748.4	c.940+122A>C		intron_variant		ENST00000375341.8
ALDH4A1	NM_001161504.2	c.760+122A>C		intron_variant
ALDH4A1	NM_001319218.2	c.940+122A>C		intron_variant
ALDH4A1	NM_170726.3	c.940+122A>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH4A1	ENST00000375341.8	c.940+122A>C		intron_variant		1	NM_003748.4	P1
ALDH4A1	ENST00000290597.9	c.940+122A>C		intron_variant		1		P1
ALDH4A1	ENST00000538839.5	c.940+122A>C		intron_variant		1
ALDH4A1	ENST00000538309.5	c.760+122A>C		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.427 AC: 64876 AN: 151922 Hom.: 14310 Cov.: 32

Gnomad AFR AF: 0.489

Gnomad AMI AF: 0.335

Gnomad AMR AF: 0.467

Gnomad ASJ AF: 0.238

Gnomad EAS AF: 0.364

Gnomad SAS AF: 0.423

Gnomad FIN AF: 0.515

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.384

Gnomad OTH AF: 0.414

GnomAD4 exome AF: 0.389 AC: 309280 AN: 795722 Hom.: 61773 AF XY: 0.387 AC XY: 157781 AN XY: 407868

Gnomad4 AFR exome AF: 0.495

Gnomad4 AMR exome AF: 0.462

Gnomad4 ASJ exome AF: 0.243

Gnomad4 EAS exome AF: 0.310

Gnomad4 SAS exome AF: 0.403

Gnomad4 FIN exome AF: 0.508

Gnomad4 NFE exome AF: 0.379

Gnomad4 OTH exome AF: 0.382

GnomAD4 genome AF: 0.427 AC: 64944 AN: 152040 Hom.: 14332 Cov.: 32 AF XY: 0.435 AC XY: 32302 AN XY: 74318

Gnomad4 AFR AF: 0.489

Gnomad4 AMR AF: 0.467

Gnomad4 ASJ AF: 0.238

Gnomad4 EAS AF: 0.364

Gnomad4 SAS AF: 0.424

Gnomad4 FIN AF: 0.515

Gnomad4 NFE AF: 0.384

Gnomad4 OTH AF: 0.414

Alfa AF: 0.385 Hom.: 11609

Bravo AF: 0.420

Asia WGS AF: 0.410 AC: 1427 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.13
DANN	Benign	0.80

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: rs28497538; hg19: chr1-19205672;