rs137852308

Variant names:

• chrX-55021215-C-A
• rs137852308
• NM_000032.5:c.475G>T

Your query was ambiguous. Multiple possible variants found:

• chrX-55021215-C-A
• chrX-55021215-C-T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_000032.5(ALAS2):​c.475G>T​(p.Asp159Tyr) 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D159N) has been classified as Pathogenic.

• 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
• Publications: 11 publications found

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 Gene-Disease associations (from GenCC):

• X-linked erythropoietic protoporphyria

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• X-linked sideroblastic anemia 1

  Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000032.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-55021215-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 10479.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974
• PP5: Variant X-55021215-C-A is Pathogenic according to our data. Variant chrX-55021215-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 10478.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALAS2	NM_000032.5	c.475G>T	p.Asp159Tyr	missense_variant	Exon 5 of 11	ENST00000650242.1	NP_000023.2
ALAS2	NM_001037968.4	c.436G>T	p.Asp146Tyr	missense_variant	Exon 5 of 11		NP_001033057.1
ALAS2	NM_001037967.4	c.364G>T	p.Asp122Tyr	missense_variant	Exon 4 of 10		NP_001033056.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALAS2	ENST00000650242.1	c.475G>T	p.Asp159Tyr	missense_variant	Exon 5 of 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

Jul 01, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.68	D
BayesDel_noAF	Pathogenic	0.74
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	.;D;D;.;.;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;.;D;D;D;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D
MetaSVM	Uncertain	0.053	D
MutationAssessor	Pathogenic	3.1	.;M;M;.;.;.
PhyloP100		7.9
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-8.4	D;.;D;D;.;.
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;.;D;D;.;.
Sift4G	Pathogenic	0.0	D;.;D;D;.;.
Polyphen		1.0	.;D;D;.;.;.
Vest4		0.87
MutPred		0.82		.;Loss of disorder (P = 0.036);Loss of disorder (P = 0.036);.;.;.;
MVP		0.99
MPC		1.6
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.97
gMVP		0.99
Mutation Taster		=2/98	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs137852308; hg19: chrX-55047648;