X-55009279-G-GCAGGCAGCCACAGACACAT

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_000032.5(ALAS2):c.1664_1665insATGTGTCTGTGGCTGCCTG(p.Cys555Ter) variant causes a stop gained, frameshift 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 stop_gained, frameshift
• 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 8 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. There are 6 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	UniProt
ALAS2	NM_000032.5	c.1664_1665insATGTGTCTGTGGCTGCCTG	p.Cys555Ter	stop_gained, frameshift_variant	11/11	ENST00000650242.1
ALAS2	NM_001037967.4	c.1553_1554insATGTGTCTGTGGCTGCCTG	p.Cys518Ter	stop_gained, frameshift_variant	10/10
ALAS2	NM_001037968.4	c.1625_1626insATGTGTCTGTGGCTGCCTG	p.Cys542Ter	stop_gained, frameshift_variant	11/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALAS2	ENST00000650242.1	c.1664_1665insATGTGTCTGTGGCTGCCTG	p.Cys555Ter	stop_gained, frameshift_variant	11/11		NM_000032.5	P1
ALAS2	ENST00000335854.8	c.1553_1554insATGTGTCTGTGGCTGCCTG	p.Cys518Ter	stop_gained, frameshift_variant	10/10	2
ALAS2	ENST00000396198.7	c.1625_1626insATGTGTCTGTGGCTGCCTG	p.Cys542Ter	stop_gained, frameshift_variant	11/11	5
ALAS2	ENST00000498636.1	c.792_793insATGTGTCTGTGGCTGCCTG	p.Ala265AspfsTer40	frameshift_variant	5/5	3

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;