NM_000032.5:c.1354C>T

Variant names:

• chrX-55014830-G-A
• rs137852311
• NM_000032.5:c.1354C>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000032.5(ALAS2):​c.1354C>T​(p.Arg452Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000183 in 1,090,557 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R452L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
• Consequence: ALAS2 NM_000032.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 6.32
• Publications: 18 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 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-55014829-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2690508.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974
• PP5: Variant X-55014830-G-A is Pathogenic according to our data. Variant chrX-55014830-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 10485.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALAS2	NM_000032.5	c.1354C>T	p.Arg452Cys	missense_variant	Exon 9 of 11	ENST00000650242.1	NP_000023.2
ALAS2	NM_001037968.4	c.1315C>T	p.Arg439Cys	missense_variant	Exon 9 of 11		NP_001033057.1
ALAS2	NM_001037967.4	c.1243C>T	p.Arg415Cys	missense_variant	Exon 8 of 10		NP_001033056.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALAS2	ENST00000650242.1	c.1354C>T	p.Arg452Cys	missense_variant	Exon 9 of 11		NM_000032.5	ENSP00000497236.1
ALAS2	ENST00000396198.7	c.1315C>T	p.Arg439Cys	missense_variant	Exon 9 of 11	5		ENSP00000379501.3
ALAS2	ENST00000335854.8	c.1243C>T	p.Arg415Cys	missense_variant	Exon 8 of 10	2		ENSP00000337131.4
ALAS2	ENST00000498636.1	c.643C>T	p.Arg215Cys	missense_variant	Exon 4 of 5	3		ENSP00000495662.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.00000183 AC: 2 AN: 1090557 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 357139

African (AFR) AF: 0.00 AC: 0 AN: 26256

American (AMR) AF: 0.00 AC: 0 AN: 34408

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19215

East Asian (EAS) AF: 0.00 AC: 0 AN: 29850

South Asian (SAS) AF: 0.00 AC: 0 AN: 52699

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40009

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4029

European-Non Finnish (NFE) AF: 0.00000239 AC: 2 AN: 838328

Other (OTH) AF: 0.00 AC: 0 AN: 45763

GnomAD4 genome Cov.: 24

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Feb 21, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate R452C interferes with the cofactor and succinyl-CoA binding ability of the ALAS2 protein (PMID: 22740690); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 7592563, 21800356, 10029606, 24323989, 21309041, 16343269, 21252495, 16540354, 22983749, 32605921, 22740690) -

Sep 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 452 of the ALAS2 protein (p.Arg452Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with X-linked congenital sideroblastic anemia (PMID: 7592563, 21309041, 32297424). ClinVar contains an entry for this variant (Variation ID: 10485). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ALAS2 protein function. Experimental studies have shown that this missense change affects ALAS2 function (PMID: 22740690). This variant disrupts the p.Arg452 amino acid residue in ALAS2. Other variant(s) that disrupt this residue have been observed in individuals with ALAS2-related conditions (PMID: 7592563, 21309041, 32297424), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

X-linked sideroblastic anemia 1 Pathogenic:2

Mar 01, 1999

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dec 24, 2024

BloodGenetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

ALAS2-related disorder Pathogenic:1

Sep 16, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ALAS2 c.1354C>T variant is predicted to result in the amino acid substitution p.Arg452Cys. This variant was reported in individuals with sideroblastic anemia (see, for example, Bottomley et al. 1995. PubMed ID: 7592563; Cotter et al. 1999. PubMed ID: 10029606; Liu et al. 2013. PubMed ID: 24323989; Ravindra et al. 2020. PubMed ID: 32605921). In vitro functional studies indicate that the p.Arg452Cys variant protein results in loss of positive cooperativity for succinyl-CoA binding and has reduced vitamin B6 affinity (Bishop et al. 2012. PubMed ID: 22740690). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	.;D;D;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;.;D;D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.4	.;M;M;.
PhyloP100		6.3
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-4.3	D;.;D;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0080	D;.;D;D
Sift4G	Uncertain	0.013	D;.;D;D
Polyphen		1.0	.;D;D;.
Vest4		0.69
MutPred		0.87		.;Loss of disorder (P = 0.0145);Loss of disorder (P = 0.0145);.;
MVP		0.99
MPC		1.6
ClinPred		0.99	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.85
gMVP		0.94
Mutation Taster		=0/100	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: rs137852311; hg19: chrX-55041263;