rs140772352

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The XM_011530785.3(PAGE2B):c.61+1512G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00655 in 181,091 control chromosomes in the GnomAD database, including 3 homozygotes. There are 263 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0065 ( 3 hom., 175 hem., cov: 22)

Exomes 𝑓: 0.0067 ( 0 hom. 88 hem. )

Consequence

PAGE2B
XM_011530785.3 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:6

Conservation

PhyloP100: 0.404

Publications

1 publications found

Variant links:

Genes affected

PAGE2B (HGNC:31805): (PAGE family member 2B)

PAGE2B links:

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: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant X-55031184-G-C is Benign according to our data. Variant chrX-55031184-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 10480.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALAS2	NM_000032.5 link	c.-258C>G		upstream_gene_variant		ENST00000650242.1	NP_000023.2	P22557-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALAS2	ENST00000650242.1 link	c.-258C>G		upstream_gene_variant			NM_000032.5	ENSP00000497236.1		P22557-1

Frequencies

GnomAD3 genomes

AF:

0.00647

AC:

720

AN:

111336

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00582

Gnomad ASJ

AF:

0.0194

Gnomad EAS

AF:

0.000281

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.00535

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00922

Gnomad OTH

AF:

0.0120

GnomAD4 exome

AF:

0.00669

AC:

466

AN:

69705

Hom.:

AF XY:

0.00598

AC XY:

AN XY:

14711

show subpopulations

African (AFR)

AF:

0.00116

AC:

AN:

2583

American (AMR)

AF:

0.00809

AC:

AN:

4325

Ashkenazi Jewish (ASJ)

AF:

0.0147

AC:

AN:

1635

East Asian (EAS)

AF:

0.00

AC:

AN:

3528

South Asian (SAS)

AF:

0.00328

AC:

AN:

9146

European-Finnish (FIN)

AF:

0.00431

AC:

AN:

3245

Middle Eastern (MID)

AF:

0.00481

AC:

AN:

208

European-Non Finnish (NFE)

AF:

0.00798

AC:

331

AN:

41480

Other (OTH)

AF:

0.00788

AC:

AN:

3555

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

102

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.00646

AC:

720

AN:

111386

Hom.:

Cov.:

AF XY:

0.00521

AC XY:

175

AN XY:

33602

show subpopulations

African (AFR)

AF:

0.00193

AC:

AN:

30636

American (AMR)

AF:

0.00581

AC:

AN:

10495

Ashkenazi Jewish (ASJ)

AF:

0.0194

AC:

AN:

2634

East Asian (EAS)

AF:

0.000281

AC:

AN:

3554

South Asian (SAS)

AF:

0.00229

AC:

AN:

2620

European-Finnish (FIN)

AF:

0.00535

AC:

AN:

5985

Middle Eastern (MID)

AF:

0.0139

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.00922

AC:

489

AN:

53049

Other (OTH)

AF:

0.0119

AC:

AN:

1513

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

103

129

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.00713

Hom.:

Bravo

AF:

0.00640

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 26, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nucleotide substitution has no predicted effect on splicing and is not conserved across species; This variant is associated with the following publications: (PMID: 23935018, 25910213, 12663458, 32641076) -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ALAS2: BS1, BS2 -

Jan 05, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

X-linked sideroblastic anemia 1

Pathogenic:1

Jul 15, 2003

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

ALAS2-related disorder

Benign:1

Mar 21, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

2.8

(source)

DANN

Benign

0.64

PhyloP100

0.40

PromoterAI

0.012

Neutral

(source)

Splicing

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over