XM_011530785.3:c.61+1512G>C

Variant names:

• chrX-55031184-G-C
• rs140772352
• XM_011530785.3:c.61+1512G>C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:6
• Conservation: PhyloP100: 0.404

Genes affected

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

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 Benign. Variant got -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 [Likely_benign]. Clinvar id 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	c.-258C>G		upstream_gene_variant		ENST00000650242.1	NP_000023.2

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00647 AC: 720 AN: 111336 Hom.: 3 Cov.: 22 AF XY: 0.00522 AC XY: 175 AN XY: 33542

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.: 0 AF XY: 0.00598 AC XY: 88 AN XY: 14711

Gnomad4 AFR exome AF: 0.00116

Gnomad4 AMR exome AF: 0.00809

Gnomad4 ASJ exome AF: 0.0147

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00328

Gnomad4 FIN exome AF: 0.00431

Gnomad4 NFE exome AF: 0.00798

Gnomad4 OTH exome AF: 0.00788

GnomAD4 genome AF: 0.00646 AC: 720 AN: 111386 Hom.: 3 Cov.: 22 AF XY: 0.00521 AC XY: 175 AN XY: 33602

Gnomad4 AFR AF: 0.00193

Gnomad4 AMR AF: 0.00581

Gnomad4 ASJ AF: 0.0194

Gnomad4 EAS AF: 0.000281

Gnomad4 SAS AF: 0.00229

Gnomad4 FIN AF: 0.00535

Gnomad4 NFE AF: 0.00922

Gnomad4 OTH AF: 0.0119

Alfa AF: 0.00713 Hom.: 37

Bravo AF: 0.00640

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ALAS2: BS1, BS2 -

-

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) -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
DANN	Benign	0.64

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs140772352; hg19: chrX-55057617;