rs137852301

Variant names:

• chrX-55021195-G-T
• rs137852301
• NM_000032.5:c.495C>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_000032.5(ALAS2):​c.495C>A​(p.Phe165Leu) variant causes a missense change. 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 (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: ALAS2 NM_000032.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 4.27
• Publications: 4 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 10 ACMG points.

• PM1: In a hotspot region, there are 6 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972
• PP5: Variant X-55021195-G-T is Pathogenic according to our data. Variant chrX-55021195-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 10470.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALAS2	NM_000032.5	c.495C>A	p.Phe165Leu	missense_variant	Exon 5 of 11	ENST00000650242.1	NP_000023.2
ALAS2	NM_001037968.4	c.456C>A	p.Phe152Leu	missense_variant	Exon 5 of 11		NP_001033057.1
ALAS2	NM_001037967.4	c.384C>A	p.Phe128Leu	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.495C>A	p.Phe165Leu	missense_variant	Exon 5 of 11		NM_000032.5	ENSP00000497236.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Apr 08, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ALAS2 protein function. This sequence change replaces phenylalanine with leucine at codon 165 of the ALAS2 protein (p.Phe165Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with X-linked sideroblastic anemia (PMID: 7949148). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 10470). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects ALAS2 protein function (PMID: 7949148). -

X-linked sideroblastic anemia 1 Pathogenic:1

Sep 21, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.63
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	.;D;D;.;.;.
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D;.;D;D;D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Pathogenic	3.1	.;M;M;.;.;.
PhyloP100		4.3
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-5.9	D;.;D;D;.;.
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D;.;D;D;.;.
Sift4G	Pathogenic	0.0010	D;.;D;D;.;.
Polyphen		0.99	.;D;D;.;.;.
Vest4		0.71
MutPred		0.87		.;Loss of methylation at K166 (P = 0.0384);Loss of methylation at K166 (P = 0.0384);.;.;.;
MVP		1.0
MPC		1.5
ClinPred		1.0	D
GERP RS		3.1
Varity_R		0.97
gMVP		0.99
Mutation Taster		=11/89	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: rs137852301; hg19: chrX-55047628;