rs387906472

chrX-55009234-CCACT-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1_Moderate PP5_Very_Strong

The NM_000032.5(ALAS2):c.1706_1709del(p.Glu569GlyfsTer24) variant causes a frameshift change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: ALAS2 NM_000032.5 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 7.91

Genes affected

ALAS2 (HGNC:397): (5'-aminolevulinate synthase 2) The product of this gene specifies an erythroid-specific mitochondrially located enzyme. The encoded protein catalyzes the first step in the heme biosynthetic pathway. Defects in this gene cause X-linked pyridoxine-responsive sideroblastic anemia. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0329 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PP5: Variant X-55009234-CCACT-C is Pathogenic according to our data. Variant chrX-55009234-CCACT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 10482.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALAS2	NM_000032.5	c.1706_1709del	p.Glu569GlyfsTer24	frameshift_variant	11/11	ENST00000650242.1
ALAS2	NM_001037967.4	c.1595_1598del	p.Glu532GlyfsTer24	frameshift_variant	10/10
ALAS2	NM_001037968.4	c.1667_1670del	p.Glu556GlyfsTer24	frameshift_variant	11/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALAS2	ENST00000650242.1	c.1706_1709del	p.Glu569GlyfsTer24	frameshift_variant	11/11		NM_000032.5	P1
ALAS2	ENST00000335854.8	c.1595_1598del	p.Glu532GlyfsTer24	frameshift_variant	10/10	2
ALAS2	ENST00000396198.7	c.1667_1670del	p.Glu556GlyfsTer24	frameshift_variant	11/11	5
ALAS2	ENST00000498636.1	c.*4_*7del		3_prime_UTR_variant	5/5	3

Frequencies

GnomAD3 genomes Cov.: 22

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

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

X-linked erythropoietic protoporphyria Pathogenic:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2013	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2023

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this frameshift affects ALAS2 function (PMID: 23263862). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 10482). This frameshift has been observed in individual(s) with X-linked dominant erythropoietic protoporphyria (PMID: 18760763). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change results in a frameshift in the ALAS2 gene (p.Glu569Glyfs*24). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 19 amino acid(s) of the ALAS2 protein and extend the protein by 4 additional amino acid residues. -

Erythema Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Dec 20, 2021

ACMG categories: PVS1,PM2 -

Computational scores

Source: dbNSFP v4.3

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: rs387906472; hg19: chrX-55035667;