rs164641

Positions:

• chr3-52207213-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000688.6(ALAS1):​c.1165+462T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0623 in 151,874 control chromosomes in the GnomAD database, including 377 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 0.062 (377 hom., cov: 31)
• Consequence: ALAS1 NM_000688.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.03

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0981 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALAS1	NM_000688.6	c.1165+462T>C		intron_variant		ENST00000484952.6	NP_000679.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALAS1	ENST00000484952.6	c.1165+462T>C		intron_variant		1	NM_000688.6	ENSP00000418779	P1

Frequencies

GnomAD3 genomes AF: 0.0623 AC: 9452 AN: 151756 Hom.: 375 Cov.: 31

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.150

Gnomad AMR AF: 0.0578

Gnomad ASJ AF: 0.0332

Gnomad EAS AF: 0.0337

Gnomad SAS AF: 0.0346

Gnomad FIN AF: 0.0209

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0510

Gnomad OTH AF: 0.0576

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

GnomAD4 genome AF: 0.0623 AC: 9460 AN: 151874 Hom.: 377 Cov.: 31 AF XY: 0.0603 AC XY: 4478 AN XY: 74252

Gnomad4 AFR AF: 0.101

Gnomad4 AMR AF: 0.0577

Gnomad4 ASJ AF: 0.0332

Gnomad4 EAS AF: 0.0332

Gnomad4 SAS AF: 0.0344

Gnomad4 FIN AF: 0.0209

Gnomad4 NFE AF: 0.0510

Gnomad4 OTH AF: 0.0599

Alfa AF: 0.0534 Hom.: 33

Bravo AF: 0.0671

Asia WGS AF: 0.0420 AC: 147 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	2.5
DANN	Benign	0.76

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

Publications

LitVar

Other links and lift over

dbSNP: rs164641; hg19: chr3-52241229;