X-55009279-G-GCAGGCAGCCACAGACACAT

Position:

• chrX-55009279-G-GCAGGCAGCCACAGACACAT

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_000032.5(ALAS2):​c.1646_1664dupATGTGTCTGTGGCTGCCTG​(p.Cys555fs) variant causes a frameshift, stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: ALAS2 NM_000032.5 frameshift, stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P: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 Likely_pathogenic. Variant got 6 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 0.0567 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-55009279-G-GCAGGCAGCCACAGACACAT is Pathogenic according to our data. Variant chrX-55009279-G-GCAGGCAGCCACAGACACAT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2683635.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALAS2	NM_000032.5	c.1646_1664dupATGTGTCTGTGGCTGCCTG	p.Cys555fs	frameshift_variant, stop_gained	11/11	ENST00000650242.1	NP_000023.2
ALAS2	NM_001037968.4	c.1607_1625dupATGTGTCTGTGGCTGCCTG	p.Cys542fs	frameshift_variant, stop_gained	11/11		NP_001033057.1
ALAS2	NM_001037967.4	c.1535_1553dupATGTGTCTGTGGCTGCCTG	p.Cys518fs	frameshift_variant, stop_gained	10/10		NP_001033056.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALAS2	ENST00000650242.1	c.1646_1664dupATGTGTCTGTGGCTGCCTG	p.Cys555fs	frameshift_variant, stop_gained	11/11		NM_000032.5	ENSP00000497236.1
ALAS2	ENST00000396198.7	c.1607_1625dupATGTGTCTGTGGCTGCCTG	p.Cys542fs	frameshift_variant, stop_gained	11/11	5		ENSP00000379501.3
ALAS2	ENST00000335854.8	c.1535_1553dupATGTGTCTGTGGCTGCCTG	p.Cys518fs	frameshift_variant, stop_gained	10/10	2		ENSP00000337131.4
ALAS2	ENST00000498636.1	c.772_790dupATGTGTCTGTGGCTGCCTG	p.Ala264fs	frameshift_variant	5/5	3		ENSP00000495662.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Mar 25, 2022

PM2, PVS1_strong -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-55035712;