rs352167

Variant names:

• chr3-52204640-T-C
• rs352167
• NM_000688.6:c.578-53T>C

Variant summary

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

The NM_000688.6(ALAS1):​c.578-53T>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
• 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=-0.88).
• 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 rank	MANE	Protein	UniProt
ALAS1	NM_000688.6	c.578-53T>C		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.578-53T>C		intron_variant	Intron 5 of 11	1	NM_000688.6	ENSP00000418779.1
ALAS1	ENST00000310271.6	c.578-53T>C		intron_variant	Intron 4 of 10	1		ENSP00000309259.2
ALAS1	ENST00000469224.5	c.578-53T>C		intron_variant	Intron 4 of 10	1		ENSP00000417719.1
ALAS1	ENST00000394965.6	c.578-53T>C		intron_variant	Intron 5 of 11	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

African (AFR) AF: 0.451 AC: 13731 AN: 30436

American (AMR) AF: 0.531 AC: 21951 AN: 41306

Ashkenazi Jewish (ASJ) AF: 0.549 AC: 13705 AN: 24972

East Asian (EAS) AF: 0.444 AC: 16772 AN: 37738

South Asian (SAS) AF: 0.410 AC: 33210 AN: 81038

European-Finnish (FIN) AF: 0.502 AC: 23674 AN: 47194

Middle Eastern (MID) AF: 0.499 AC: 2729 AN: 5464

European-Non Finnish (NFE) AF: 0.539 AC: 545110 AN: 1011548

Other (OTH) AF: 0.502 AC: 28142 AN: 56042

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

African (AFR) AF: 0.449 AC: 18641 AN: 41496

American (AMR) AF: 0.522 AC: 7985 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.546 AC: 1894 AN: 3468

East Asian (EAS) AF: 0.390 AC: 2018 AN: 5178

South Asian (SAS) AF: 0.416 AC: 2006 AN: 4826

European-Finnish (FIN) AF: 0.485 AC: 5136 AN: 10582

Middle Eastern (MID) AF: 0.503 AC: 148 AN: 294

European-Non Finnish (NFE) AF: 0.539 AC: 36688 AN: 68014

Other (OTH) AF: 0.503 AC: 1058 AN: 2104

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
PhyloP100		-1.7
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: rs352167; hg19: chr3-52238656; COSMIC: COSV59628268; COSMIC: COSV59628268;