rs352169

chr3-52202746-G-Achr3-52202746-G-C

Variant summary

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

The NM_000688.6(ALAS1):c.427+12G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.506 in 1,610,236 control chromosomes in the GnomAD database, including 209,716 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 0.46 (16741 hom., cov: 32)
  • Exomes 𝑓: 0.51 (192975 hom.)
• Consequence: ALAS1 NM_000688.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.158

Genes affected

ALAS1 (HGNC:396): (5'-aminolevulinate synthase 1) This gene encodes the mitochondrial enzyme which is catalyzes the rate-limiting step in heme (iron-protoporphyrin) biosynthesis. The enzyme encoded by this gene is the housekeeping enzyme; a separate gene encodes a form of the enzyme that is specific for erythroid tissue. The level of the mature encoded protein is regulated by heme: high levels of heme down-regulate the mature enzyme in mitochondria while low heme levels up-regulate. A pseudogene of this gene is located on chromosome 12. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jan 2015]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.529 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALAS1	NM_000688.6	c.427+12G>A		intron_variant		ENST00000484952.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALAS1	ENST00000484952.6	c.427+12G>A		intron_variant		1	NM_000688.6	P1
ALAS1	ENST00000310271.6	c.427+12G>A		intron_variant		1		P1
ALAS1	ENST00000469224.5	c.427+12G>A		intron_variant		1		P1
ALAS1	ENST00000394965.6	c.427+12G>A		intron_variant		2		P1

Frequencies

GnomAD3 genomes AF: 0.457 AC: 69514 AN: 151950 Hom.: 16731 Cov.: 32

Gnomad AFR AF: 0.314

Gnomad AMI AF: 0.612

Gnomad AMR AF: 0.502

Gnomad ASJ AF: 0.543

Gnomad EAS AF: 0.386

Gnomad SAS AF: 0.388

Gnomad FIN AF: 0.484

Gnomad MID AF: 0.497

Gnomad NFE AF: 0.534

Gnomad OTH AF: 0.483

GnomAD3 exomes AF: 0.486 AC: 118736 AN: 244540 Hom.: 29497 AF XY: 0.484 AC XY: 64110 AN XY: 132454

Gnomad AFR exome AF: 0.316

Gnomad AMR exome AF: 0.524

Gnomad ASJ exome AF: 0.543

Gnomad EAS exome AF: 0.372

Gnomad SAS exome AF: 0.384

Gnomad FIN exome AF: 0.497

Gnomad NFE exome AF: 0.536

Gnomad OTH exome AF: 0.507

GnomAD4 exome AF: 0.512 AC: 745918 AN: 1458168 Hom.: 192975 Cov.: 36 AF XY: 0.508 AC XY: 368459 AN XY: 724802

Gnomad4 AFR exome AF: 0.311

Gnomad4 AMR exome AF: 0.521

Gnomad4 ASJ exome AF: 0.546

Gnomad4 EAS exome AF: 0.440

Gnomad4 SAS exome AF: 0.383

Gnomad4 FIN exome AF: 0.500

Gnomad4 NFE exome AF: 0.531

Gnomad4 OTH exome AF: 0.486

GnomAD4 genome AF: 0.457 AC: 69559 AN: 152068 Hom.: 16741 Cov.: 32 AF XY: 0.454 AC XY: 33706 AN XY: 74318

Gnomad4 AFR AF: 0.314

Gnomad4 AMR AF: 0.501

Gnomad4 ASJ AF: 0.543

Gnomad4 EAS AF: 0.386

Gnomad4 SAS AF: 0.389

Gnomad4 FIN AF: 0.484

Gnomad4 NFE AF: 0.534

Gnomad4 OTH AF: 0.484

Alfa AF: 0.521 Hom.: 44453

Bravo AF: 0.455

Asia WGS AF: 0.403 AC: 1401 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	4.7
Dann	Benign	0.66

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: rs352169; hg19: chr3-52236762; COSMIC: COSV59628258; COSMIC: COSV59628258;