Genetic Variant ALAS2:p.Arg452Ser (chrX-55014830-G-T) – ACMG Classification: Pathogenic (14 pts)

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000032.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ALAS2	NM_000032.5	MANE Select	c.1354C>A	p.Arg452Ser	missense	Exon 9 of 11	NP_000023.2	P22557-1
ALAS2	NM_001037968.4		c.1315C>A	p.Arg439Ser	missense	Exon 9 of 11	NP_001033057.1	P22557-4
ALAS2	NM_001037967.4		c.1243C>A	p.Arg415Ser	missense	Exon 8 of 10	NP_001033056.1	P22557-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ALAS2	ENST00000650242.1	MANE Select	c.1354C>A	p.Arg452Ser	missense	Exon 9 of 11	ENSP00000497236.1	P22557-1
ALAS2	ENST00000396198.7	TSL:5	c.1315C>A	p.Arg439Ser	missense	Exon 9 of 11	ENSP00000379501.3	P22557-4
ALAS2	ENST00000335854.8	TSL:2	c.1243C>A	p.Arg415Ser	missense	Exon 8 of 10	ENSP00000337131.4	P22557-2

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

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Computational scores

Source: dbNSFP v4.9

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

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

M_CAP

Pathogenic

0.81

MetaRNN

Pathogenic

0.90

MetaSVM

Uncertain

0.16

MutationAssessor

Benign

0.20

PhyloP100

6.3

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-2.1

REVEL

Pathogenic

0.74

Sift

Benign

0.17

Sift4G

Benign

0.27

Polyphen

0.80

Vest4

0.91

MutPred

0.87

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over