rs397514730

Positions:

• chrX-55009302-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_000032.5(ALAS2):​c.1642C>T​(p.Gln548Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 23)
• Consequence: ALAS2 NM_000032.5 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.88

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 7 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 7 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-55009302-G-A is Pathogenic according to our data. Variant chrX-55009302-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 60673.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALAS2	NM_000032.5	c.1642C>T	p.Gln548Ter	stop_gained	11/11	ENST00000650242.1
ALAS2	NM_001037968.4	c.1603C>T	p.Gln535Ter	stop_gained	11/11
ALAS2	NM_001037967.4	c.1531C>T	p.Gln511Ter	stop_gained	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALAS2	ENST00000650242.1	c.1642C>T	p.Gln548Ter	stop_gained	11/11		NM_000032.5	P1
ALAS2	ENST00000396198.7	c.1603C>T	p.Gln535Ter	stop_gained	11/11	5
ALAS2	ENST00000335854.8	c.1531C>T	p.Gln511Ter	stop_gained	10/10	2
ALAS2	ENST00000498636.1	c.771C>T	p.Ser257=	synonymous_variant	5/5	3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

X-linked erythropoietic protoporphyria Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	38
DANN	Uncertain	0.98
FATHMM_MKL	Uncertain	0.88	D
MutationTaster	Benign	1.0	D;D;D
Vest4		0.70
GERP RS		3.5
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs397514730; hg19: chrX-55035735;