rs137852301

Positions:

• chrX-55021195-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. 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

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 8 ACMG points.

• 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 id is 10470.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALAS2	NM_000032.5	c.495C>A	p.Phe165Leu	missense_variant	5/11	ENST00000650242.1	NP_000023.2
ALAS2	NM_001037968.4	c.456C>A	p.Phe152Leu	missense_variant	5/11		NP_001033057.1
ALAS2	NM_001037967.4	c.384C>A	p.Phe128Leu	missense_variant	4/10		NP_001033056.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALAS2	ENST00000650242.1	c.495C>A	p.Phe165Leu	missense_variant	5/11		NM_000032.5	ENSP00000497236	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 08, 2021

Experimental studies have shown that this variant affects ALAS2 protein function (PMID: 7949148). For these reasons, this variant has been classified as Pathogenic. 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 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). This variant is not present in population databases (ExAC no frequency). 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. -

X-linked sideroblastic anemia 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 21, 2005

- -

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;.;.;.
MutationTaster	Benign	1.0	A;A;A
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

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: rs137852301; hg19: chrX-55047628;