3-52213094-G-A

Variant names:

• chr3-52213094-G-A
• rs352163
• NM_000688.6:c.1762+674G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000688.6(ALAS1):​c.1762+674G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.476 in 151,900 control chromosomes in the GnomAD database, including 17,782 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 0.48 (17782 hom., cov: 31)
• Consequence: ALAS1 NM_000688.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.208
• Publications: 16 publications found

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]

ENSG00000296921 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 = 0.531 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000688.6. 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
	ALAS1	NM_000688.6	MANE Select	c.1762+674G>A		intron	N/A	NP_000679.1
	ALAS1	NM_001304444.1		c.1813+674G>A		intron	N/A	NP_001291373.1
	ALAS1	NM_001304443.1		c.1762+674G>A		intron	N/A	NP_001291372.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALAS1	ENST00000484952.6	TSL:1 MANE Select	c.1762+674G>A		intron	N/A	ENSP00000418779.1
	ALAS1	ENST00000310271.6	TSL:1	c.1762+674G>A		intron	N/A	ENSP00000309259.2
	ALAS1	ENST00000469224.5	TSL:1	c.1762+674G>A		intron	N/A	ENSP00000417719.1

Frequencies

GnomAD3 genomes AF: 0.476 AC: 72245 AN: 151782 Hom.: 17772 Cov.: 31

Gnomad AFR AF: 0.369

Gnomad AMI AF: 0.612

Gnomad AMR AF: 0.508

Gnomad ASJ AF: 0.543

Gnomad EAS AF: 0.386

Gnomad SAS AF: 0.420

Gnomad FIN AF: 0.494

Gnomad MID AF: 0.497

Gnomad NFE AF: 0.536

Gnomad OTH AF: 0.493

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.476 AC: 72286 AN: 151900 Hom.: 17782 Cov.: 31 AF XY: 0.472 AC XY: 35051 AN XY: 74222

African (AFR) AF: 0.369 AC: 15285 AN: 41412

American (AMR) AF: 0.507 AC: 7735 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.543 AC: 1887 AN: 3472

East Asian (EAS) AF: 0.386 AC: 1998 AN: 5172

South Asian (SAS) AF: 0.421 AC: 2029 AN: 4818

European-Finnish (FIN) AF: 0.494 AC: 5213 AN: 10550

Middle Eastern (MID) AF: 0.493 AC: 144 AN: 292

European-Non Finnish (NFE) AF: 0.536 AC: 36398 AN: 67926

Other (OTH) AF: 0.494 AC: 1041 AN: 2106

Alfa AF: 0.511 Hom.: 32878

Bravo AF: 0.474

Asia WGS AF: 0.414 AC: 1440 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.95
DANN	Benign	0.69
PhyloP100		-0.21
Mutation Taster		=100/0	polymorphism (auto)

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: rs352163; hg19: chr3-52247110;