3-52202061-A-G

Variant names:

• chr3-52202061-A-G
• rs352170
• NM_000688.6:c.200-446A>G

Variant summary

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

The NM_000688.6(ALAS1):​c.200-446A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.467 in 152,100 control chromosomes in the GnomAD database, including 17,184 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 0.47 (17184 hom., cov: 33)
• Consequence: ALAS1 NM_000688.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.330
• Publications: 12 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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.53 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.200-446A>G		intron	N/A	NP_000679.1
	ALAS1	NM_001304444.1		c.251-446A>G		intron	N/A	NP_001291373.1
	ALAS1	NM_001304443.1		c.200-446A>G		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.200-446A>G		intron	N/A	ENSP00000418779.1
	ALAS1	ENST00000310271.6	TSL:1	c.200-446A>G		intron	N/A	ENSP00000309259.2
	ALAS1	ENST00000469224.5	TSL:1	c.200-446A>G		intron	N/A	ENSP00000417719.1

Frequencies

GnomAD3 genomes AF: 0.467 AC: 70925 AN: 151982 Hom.: 17173 Cov.: 33

Gnomad AFR AF: 0.345

Gnomad AMI AF: 0.613

Gnomad AMR AF: 0.506

Gnomad ASJ AF: 0.543

Gnomad EAS AF: 0.389

Gnomad SAS AF: 0.388

Gnomad FIN AF: 0.483

Gnomad MID AF: 0.497

Gnomad NFE AF: 0.534

Gnomad OTH AF: 0.486

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

GnomAD4 genome AF: 0.467 AC: 70974 AN: 152100 Hom.: 17184 Cov.: 33 AF XY: 0.463 AC XY: 34403 AN XY: 74334

African (AFR) AF: 0.345 AC: 14299 AN: 41464

American (AMR) AF: 0.505 AC: 7721 AN: 15290

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

East Asian (EAS) AF: 0.389 AC: 2011 AN: 5174

South Asian (SAS) AF: 0.389 AC: 1878 AN: 4824

European-Finnish (FIN) AF: 0.483 AC: 5112 AN: 10576

Middle Eastern (MID) AF: 0.493 AC: 145 AN: 294

European-Non Finnish (NFE) AF: 0.534 AC: 36333 AN: 67984

Other (OTH) AF: 0.488 AC: 1029 AN: 2110

Alfa AF: 0.514 Hom.: 26711

Bravo AF: 0.464

Asia WGS AF: 0.408 AC: 1420 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	7.0
DANN	Benign	0.74
PhyloP100		0.33
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: rs352170; hg19: chr3-52236077;