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. The variant received -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
• Publications: 1 publications found

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]

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

ACMG classification

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000650242.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALAS2	NM_000032.5	MANE Select	c.-258C>G		upstream_gene	N/A	NP_000023.2	P22557-1
	ALAS2	NM_001037968.4		c.-293C>G		upstream_gene	N/A	NP_001033057.1	P22557-4
	ALAS2	NM_001037967.4		c.-258C>G		upstream_gene	N/A	NP_001033056.1	P22557-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALAS2	ENST00000650242.1	MANE Select	c.-258C>G		upstream_gene	N/A	ENSP00000497236.1	P22557-1
	ALAS2	ENST00000396198.7	TSL:5	c.-293C>G		upstream_gene	N/A	ENSP00000379501.3	P22557-4
	ALAS2	ENST00000335854.8	TSL:2	c.-258C>G		upstream_gene	N/A	ENSP00000337131.4	P22557-2

Frequencies

GnomAD3 genomes AF: 0.00647 AC: 720 AN: 111336 Hom.: 3 Cov.: 22

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

African (AFR) AF: 0.00116 AC: 3 AN: 2583

American (AMR) AF: 0.00809 AC: 35 AN: 4325

Ashkenazi Jewish (ASJ) AF: 0.0147 AC: 24 AN: 1635

East Asian (EAS) AF: 0.00 AC: 0 AN: 3528

South Asian (SAS) AF: 0.00328 AC: 30 AN: 9146

European-Finnish (FIN) AF: 0.00431 AC: 14 AN: 3245

Middle Eastern (MID) AF: 0.00481 AC: 1 AN: 208

European-Non Finnish (NFE) AF: 0.00798 AC: 331 AN: 41480

Other (OTH) AF: 0.00788 AC: 28 AN: 3555

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

African (AFR) AF: 0.00193 AC: 59 AN: 30636

American (AMR) AF: 0.00581 AC: 61 AN: 10495

Ashkenazi Jewish (ASJ) AF: 0.0194 AC: 51 AN: 2634

East Asian (EAS) AF: 0.000281 AC: 1 AN: 3554

South Asian (SAS) AF: 0.00229 AC: 6 AN: 2620

European-Finnish (FIN) AF: 0.00535 AC: 32 AN: 5985

Middle Eastern (MID) AF: 0.0139 AC: 3 AN: 216

European-Non Finnish (NFE) AF: 0.00922 AC: 489 AN: 53049

Other (OTH) AF: 0.0119 AC: 18 AN: 1513

Alfa AF: 0.00713 Hom.: 37

Bravo AF: 0.00640

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	1	ALAS2-related disorder (1)
1	-	-	X-linked sideroblastic anemia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.8
DANN	Benign	0.64
PhyloP100		0.40
PromoterAI		0.012	Neutral

Splicing

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

Other links and lift over

dbSNP: rs140772352; hg19: chrX-55057617;