rs352167

Positions:

• chr3-52204640-T-C

Variant summary

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

The NM_000688.6(ALAS1):​c.578-53T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.521 in 1,487,906 control chromosomes in the GnomAD database, including 203,634 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 0.50 (19313 hom., cov: 34)
  • Exomes 𝑓: 0.52 (184321 hom.)
• Consequence: ALAS1 NM_000688.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.74

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=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.535 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALAS1	NM_000688.6	c.578-53T>C		intron_variant		ENST00000484952.6	NP_000679.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALAS1	ENST00000484952.6	c.578-53T>C		intron_variant		1	NM_000688.6	ENSP00000418779.1
ALAS1	ENST00000310271.6	c.578-53T>C		intron_variant		1		ENSP00000309259.2
ALAS1	ENST00000469224.5	c.578-53T>C		intron_variant		1		ENSP00000417719.1
ALAS1	ENST00000394965.6	c.578-53T>C		intron_variant		2		ENSP00000378416.2

Frequencies

GnomAD3 genomes AF: 0.500 AC: 76064 AN: 152050 Hom.: 19297 Cov.: 34

Gnomad AFR AF: 0.449

Gnomad AMI AF: 0.614

Gnomad AMR AF: 0.523

Gnomad ASJ AF: 0.546

Gnomad EAS AF: 0.390

Gnomad SAS AF: 0.414

Gnomad FIN AF: 0.485

Gnomad MID AF: 0.506

Gnomad NFE AF: 0.539

Gnomad OTH AF: 0.501

GnomAD4 exome AF: 0.523 AC: 699024 AN: 1335738 Hom.: 184321 AF XY: 0.520 AC XY: 346809 AN XY: 667224

Gnomad4 AFR exome AF: 0.451

Gnomad4 AMR exome AF: 0.531

Gnomad4 ASJ exome AF: 0.549

Gnomad4 EAS exome AF: 0.444

Gnomad4 SAS exome AF: 0.410

Gnomad4 FIN exome AF: 0.502

Gnomad4 NFE exome AF: 0.539

Gnomad4 OTH exome AF: 0.502

GnomAD4 genome AF: 0.500 AC: 76133 AN: 152168 Hom.: 19313 Cov.: 34 AF XY: 0.496 AC XY: 36916 AN XY: 74374

Gnomad4 AFR AF: 0.449

Gnomad4 AMR AF: 0.522

Gnomad4 ASJ AF: 0.546

Gnomad4 EAS AF: 0.390

Gnomad4 SAS AF: 0.416

Gnomad4 FIN AF: 0.485

Gnomad4 NFE AF: 0.539

Gnomad4 OTH AF: 0.503

Alfa AF: 0.521 Hom.: 4035

Bravo AF: 0.503

Asia WGS AF: 0.427 AC: 1486 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.60
DANN	Benign	0.60

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: rs352167; hg19: chr3-52238656; COSMIC: COSV59628268; COSMIC: COSV59628268;