X-55014830-G-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2PM5PP3_ModeratePP5_Very_Strong

The NM_000032.5(ALAS2):c.1354C>A(p.Arg452Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000166 in 1,203,105 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes 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: 𝑓 0.0000089 ( 0 hom., 1 hem., cov: 24)

Exomes 𝑓: 9.2e-7 ( 0 hom. 0 hem. )

Consequence

ALAS2
NM_000032.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 6.32

Publications

18 publications found

Variant links:

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

ALAS2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 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, 0.901

PP5

Variant X-55014830-G-T is Pathogenic according to our data. Variant chrX-55014830-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 2138581.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 link	c.1354C>A	p.Arg452Ser	missense_variant	Exon 9 of 11	ENST00000650242.1	NP_000023.2	P22557-1
ALAS2	NM_001037968.4 link	c.1315C>A	p.Arg439Ser	missense_variant	Exon 9 of 11		NP_001033057.1	P22557-4
ALAS2	NM_001037967.4 link	c.1243C>A	p.Arg415Ser	missense_variant	Exon 8 of 10		NP_001033056.1	P22557-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ALAS2	ENST00000650242.1 link	c.1354C>A	p.Arg452Ser	missense_variant	Exon 9 of 11		NM_000032.5	ENSP00000497236.1	P22557-1
ALAS2	ENST00000396198.7 link	c.1315C>A	p.Arg439Ser	missense_variant	Exon 9 of 11	5		ENSP00000379501.3	P22557-4
ALAS2	ENST00000335854.8 link	c.1243C>A	p.Arg415Ser	missense_variant	Exon 8 of 10	2		ENSP00000337131.4	P22557-2
ALAS2	ENST00000498636.1 link	c.643C>A	p.Arg215Ser	missense_variant	Exon 4 of 5	3		ENSP00000495662.1	A0A2R8Y6N3

Frequencies

GnomAD3 genomes

AF:

0.00000889

AC:

AN:

112542

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000323

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000613

AC:

AN:

163251

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.0000860

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

9.17e-7

AC:

AN:

1090563

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

357145

show subpopulations

African (AFR)

AF:

0.0000381

AC:

AN:

26256

American (AMR)

AF:

0.00

AC:

AN:

34408

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19215

East Asian (EAS)

AF:

0.00

AC:

AN:

29850

South Asian (SAS)

AF:

0.00

AC:

AN:

52699

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40009

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4029

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

838333

Other (OTH)

AF:

0.00

AC:

AN:

45764

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000889

AC:

AN:

112542

Hom.:

Cov.:

AF XY:

0.0000288

AC XY:

AN XY:

34680

show subpopulations

African (AFR)

AF:

0.0000323

AC:

AN:

30969

American (AMR)

AF:

0.00

AC:

AN:

10731

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2655

East Asian (EAS)

AF:

0.00

AC:

AN:

3562

South Asian (SAS)

AF:

0.00

AC:

AN:

2741

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6167

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53275

Other (OTH)

AF:

0.00

AC:

AN:

1519

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000826

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Aug 17, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21800356, 7592563, 19066423, 22740690) -

Jul 12, 2023

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 17, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg452 amino acid residue in ALAS2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7592563, 21309041, 32297424). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 missense change has been observed in individuals with clinical features of ALAS2-related conditions (PMID: 7592563, 19066423, 21800356). This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 452 of the ALAS2 protein (p.Arg452Ser). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.43

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.64

.;D;D;.

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

D;.;D;D

M_CAP

Pathogenic

0.81

MetaRNN

Pathogenic

0.90

D;D;D;D

MetaSVM

Uncertain

0.16

MutationAssessor

Benign

0.20

.;N;N;.

PhyloP100

6.3

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-2.1

N;.;N;N

REVEL

Pathogenic

0.74

Sift

Benign

0.17

T;.;T;T

Sift4G

Benign

0.27

T;.;T;T

Polyphen

0.80

.;P;P;.

Vest4

0.91

MutPred

0.87

.;Loss of MoRF binding (P = 0.0641);Loss of MoRF binding (P = 0.0641);.;

MVP

1.0

MPC

0.87

ClinPred

0.26

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.87

gMVP

0.96

Mutation Taster

=0/100

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over