3-52204661-C-T

Variant names:

• chr3-52204661-C-T
• rs352166
• NM_000688.6:c.578-32C>T

Variant summary

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

The NM_000688.6(ALAS1):​c.578-32C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.513 in 1,577,098 control chromosomes in the GnomAD database, including 210,280 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. There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.46 (17131 hom., cov: 33)
  • Exomes 𝑓: 0.52 (193149 hom.)
• Consequence: ALAS1 NM_000688.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.793
• Publications: 18 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: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 1 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.534 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALAS1	NM_000688.6	c.578-32C>T		intron_variant	Intron 5 of 11	ENST00000484952.6	NP_000679.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALAS1	ENST00000484952.6	c.578-32C>T		intron_variant	Intron 5 of 11	1	NM_000688.6	ENSP00000418779.1
ALAS1	ENST00000310271.6	c.578-32C>T		intron_variant	Intron 4 of 10	1		ENSP00000309259.2
ALAS1	ENST00000469224.5	c.578-32C>T		intron_variant	Intron 4 of 10	1		ENSP00000417719.1
ALAS1	ENST00000394965.6	c.578-32C>T		intron_variant	Intron 5 of 11	2		ENSP00000378416.2

Frequencies

GnomAD3 genomes AF: 0.463 AC: 70398 AN: 152060 Hom.: 17120 Cov.: 33

Gnomad AFR AF: 0.321

Gnomad AMI AF: 0.613

Gnomad AMR AF: 0.506

Gnomad ASJ AF: 0.545

Gnomad EAS AF: 0.389

Gnomad SAS AF: 0.413

Gnomad FIN AF: 0.486

Gnomad MID AF: 0.497

Gnomad NFE AF: 0.539

Gnomad OTH AF: 0.483

GnomAD2 exomes AF: 0.491 AC: 117292 AN: 238826 AF XY: 0.491

Gnomad AFR exome AF: 0.321

Gnomad AMR exome AF: 0.527

Gnomad ASJ exome AF: 0.545

Gnomad EAS exome AF: 0.375

Gnomad FIN exome AF: 0.497

Gnomad NFE exome AF: 0.540

Gnomad OTH exome AF: 0.505

GnomAD4 exome AF: 0.518 AC: 737924 AN: 1424920 Hom.: 193149 Cov.: 25 AF XY: 0.515 AC XY: 365408 AN XY: 709256

African (AFR) AF: 0.320 AC: 10397 AN: 32540

American (AMR) AF: 0.523 AC: 22915 AN: 43780

Ashkenazi Jewish (ASJ) AF: 0.548 AC: 14162 AN: 25860

East Asian (EAS) AF: 0.443 AC: 17335 AN: 39164

South Asian (SAS) AF: 0.408 AC: 34605 AN: 84754

European-Finnish (FIN) AF: 0.501 AC: 25493 AN: 50846

Middle Eastern (MID) AF: 0.494 AC: 2811 AN: 5696

European-Non Finnish (NFE) AF: 0.537 AC: 581169 AN: 1083202

Other (OTH) AF: 0.492 AC: 29037 AN: 59078

GnomAD4 genome AF: 0.463 AC: 70437 AN: 152178 Hom.: 17131 Cov.: 33 AF XY: 0.459 AC XY: 34156 AN XY: 74388

African (AFR) AF: 0.321 AC: 13306 AN: 41516

American (AMR) AF: 0.505 AC: 7727 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.545 AC: 1891 AN: 3468

East Asian (EAS) AF: 0.389 AC: 2016 AN: 5176

South Asian (SAS) AF: 0.415 AC: 2003 AN: 4832

European-Finnish (FIN) AF: 0.486 AC: 5140 AN: 10578

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

European-Non Finnish (NFE) AF: 0.539 AC: 36630 AN: 68002

Other (OTH) AF: 0.485 AC: 1020 AN: 2104

Alfa AF: 0.462 Hom.: 5681

Bravo AF: 0.459

Asia WGS AF: 0.413 AC: 1436 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	0.39
DANN	Benign	0.36
PhyloP100		-0.79
BranchPoint Hunter		1.0
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: rs352166; hg19: chr3-52238677; COSMIC: COSV59629410; COSMIC: COSV59629410;