rs137852299

Positions:

• chrX-55014757-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000032.5(ALAS2):​c.1427T>A​(p.Ile476Asn) 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: 9.25

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.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant X-55014757-A-T is Pathogenic according to our data. Variant chrX-55014757-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 10468.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.1427T>A	p.Ile476Asn	missense_variant	9/11	ENST00000650242.1	NP_000023.2
ALAS2	NM_001037968.4	c.1388T>A	p.Ile463Asn	missense_variant	9/11		NP_001033057.1
ALAS2	NM_001037967.4	c.1316T>A	p.Ile439Asn	missense_variant	8/10		NP_001033056.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALAS2	ENST00000650242.1	c.1427T>A	p.Ile476Asn	missense_variant	9/11		NM_000032.5	ENSP00000497236	P1
ALAS2	ENST00000396198.7	c.1388T>A	p.Ile463Asn	missense_variant	9/11	5		ENSP00000379501
ALAS2	ENST00000335854.8	c.1316T>A	p.Ile439Asn	missense_variant	8/10	2		ENSP00000337131
ALAS2	ENST00000498636.1	c.719T>A	p.Ile240Asn	missense_variant	4/5	3		ENSP00000495662

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

May 01, 1992

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	.;D;D;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;.;D;D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	.;H;H;.
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-6.8	D;.;D;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;.;D;D
Sift4G	Pathogenic	0.0	D;.;D;D
Polyphen		1.0	.;D;D;.
Vest4		0.91
MutPred		0.90		.;Loss of stability (P = 0.0744);Loss of stability (P = 0.0744);.;
MVP		0.96
MPC		1.9
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.99
gMVP		0.99

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: rs137852299; hg19: chrX-55041190;