X-55021215-C-T

Position:

• chrX-55021215-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_000032.5(ALAS2):​c.475G>A​(p.Asp159Asn) variant causes a missense change involving the alteration of a 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 missense
• Clinical Significance: Pathogenic no assertion criteria provided 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]

ALAS2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.81
• PP5: Variant X-55021215-C-T is Pathogenic according to our data. Variant chrX-55021215-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 10479.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALAS2	NM_000032.5	c.475G>A	p.Asp159Asn	missense_variant	5/11	ENST00000650242.1	NP_000023.2
ALAS2	NM_001037968.4	c.436G>A	p.Asp146Asn	missense_variant	5/11		NP_001033057.1
ALAS2	NM_001037967.4	c.364G>A	p.Asp122Asn	missense_variant	4/10		NP_001033056.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALAS2	ENST00000650242.1	c.475G>A	p.Asp159Asn	missense_variant	5/11		NM_000032.5	ENSP00000497236.1

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 sideroblastic anemia 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2003

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Uncertain	0.070	D
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	.;D;D;.;.;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;.;D;D;D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D;D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Uncertain	2.7	.;M;M;.;.;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-4.7	D;.;D;D;.;.
REVEL	Pathogenic	0.66
Sift	Uncertain	0.017	D;.;D;D;.;.
Sift4G	Uncertain	0.036	D;.;D;D;.;.
Polyphen		0.97	.;D;D;.;.;.
Vest4		0.83
MutPred		0.57		.;Gain of MoRF binding (P = 0.0362);Gain of MoRF binding (P = 0.0362);.;.;.;
MVP		0.97
MPC		1.0
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.79
gMVP		0.97

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: rs137852308; hg19: chrX-55047648; COSMIC: COSV58193257; COSMIC: COSV58193257;