3-52202746-G-A

Variant names:

• chr3-52202746-G-A
• rs352169
• NM_000688.6:c.427+12G>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.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
• Publications: 21 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=-0.81).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.529 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.427+12G>A		intron	N/A	NP_000679.1
	ALAS1	NM_001304444.1		c.478+12G>A		intron	N/A	NP_001291373.1
	ALAS1	NM_001304443.1		c.427+12G>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.427+12G>A		intron	N/A	ENSP00000418779.1
	ALAS1	ENST00000310271.6	TSL:1	c.427+12G>A		intron	N/A	ENSP00000309259.2
	ALAS1	ENST00000469224.5	TSL:1	c.427+12G>A		intron	N/A	ENSP00000417719.1

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

GnomAD2 exomes AF: 0.486 AC: 118736 AN: 244540 AF XY: 0.484

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 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

African (AFR) AF: 0.311 AC: 10412 AN: 33436

American (AMR) AF: 0.521 AC: 23127 AN: 44408

Ashkenazi Jewish (ASJ) AF: 0.546 AC: 14240 AN: 26094

East Asian (EAS) AF: 0.440 AC: 17431 AN: 39626

South Asian (SAS) AF: 0.383 AC: 32985 AN: 86026

European-Finnish (FIN) AF: 0.500 AC: 26514 AN: 53078

Middle Eastern (MID) AF: 0.490 AC: 2822 AN: 5754

European-Non Finnish (NFE) AF: 0.531 AC: 589098 AN: 1109486

Other (OTH) AF: 0.486 AC: 29289 AN: 60260

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

African (AFR) AF: 0.314 AC: 13039 AN: 41492

American (AMR) AF: 0.501 AC: 7655 AN: 15280

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

East Asian (EAS) AF: 0.386 AC: 1993 AN: 5166

South Asian (SAS) AF: 0.389 AC: 1876 AN: 4824

European-Finnish (FIN) AF: 0.484 AC: 5104 AN: 10554

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

European-Non Finnish (NFE) AF: 0.534 AC: 36281 AN: 67966

Other (OTH) AF: 0.484 AC: 1022 AN: 2110

Alfa AF: 0.511 Hom.: 91561

Bravo AF: 0.455

Asia WGS AF: 0.403 AC: 1401 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.7
DANN	Benign	0.66
PhyloP100		0.16
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: rs352169; hg19: chr3-52236762; COSMIC: COSV59628258; COSMIC: COSV59628258;