X-55013526-G-T

Variant names:

• chrX-55013526-G-T
• rs150055592
• NM_000032.5:c.1560C>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_000032.5(ALAS2):​c.1560C>A​(p.Pro520Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00386 in 1,209,514 control chromosomes in the GnomAD database, including 13 homozygotes. There are 1,518 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0037 (1 hom., 129 hem., cov: 22)
  • Exomes 𝑓: 0.0039 (12 hom. 1389 hem.)
• Consequence: ALAS2 NM_000032.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.216
• Publications: 1 publications found

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

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant X-55013526-G-T is Benign according to our data. Variant chrX-55013526-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 214089.
• BP7: Synonymous conserved (PhyloP=0.216 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00366 (409/111598) while in subpopulation AMR AF = 0.00694 (73/10513). AF 95% confidence interval is 0.00566. There are 1 homozygotes in GnomAd4. There are 129 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 129 XL gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALAS2	NM_000032.5	MANE Select	c.1560C>A	p.Pro520Pro	synonymous	Exon 10 of 11	NP_000023.2
	ALAS2	NM_001037968.4		c.1521C>A	p.Pro507Pro	synonymous	Exon 10 of 11	NP_001033057.1
	ALAS2	NM_001037967.4		c.1449C>A	p.Pro483Pro	synonymous	Exon 9 of 10	NP_001033056.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALAS2	ENST00000650242.1	MANE Select	c.1560C>A	p.Pro520Pro	synonymous	Exon 10 of 11	ENSP00000497236.1
	ALAS2	ENST00000396198.7	TSL:5	c.1521C>A	p.Pro507Pro	synonymous	Exon 10 of 11	ENSP00000379501.3
	ALAS2	ENST00000335854.8	TSL:2	c.1449C>A	p.Pro483Pro	synonymous	Exon 9 of 10	ENSP00000337131.4

Frequencies

GnomAD3 genomes AF: 0.00367 AC: 409 AN: 111544 Hom.: 1 Cov.: 22

Gnomad AFR AF: 0.000326

Gnomad AMI AF: 0.0160

Gnomad AMR AF: 0.00695

Gnomad ASJ AF: 0.00680

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00416

Gnomad MID AF: 0.00420

Gnomad NFE AF: 0.00495

Gnomad OTH AF: 0.00535

GnomAD2 exomes AF: 0.00365 AC: 666 AN: 182616 AF XY: 0.00359

Gnomad AFR exome AF: 0.000304

Gnomad AMR exome AF: 0.00234

Gnomad ASJ exome AF: 0.00725

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00545

Gnomad NFE exome AF: 0.00516

Gnomad OTH exome AF: 0.00576

GnomAD4 exome AF: 0.00388 AC: 4261 AN: 1097916 Hom.: 12 Cov.: 31 AF XY: 0.00382 AC XY: 1389 AN XY: 363284

African (AFR) AF: 0.000455 AC: 12 AN: 26400

American (AMR) AF: 0.00264 AC: 93 AN: 35201

Ashkenazi Jewish (ASJ) AF: 0.00650 AC: 126 AN: 19372

East Asian (EAS) AF: 0.00 AC: 0 AN: 30199

South Asian (SAS) AF: 0.000813 AC: 44 AN: 54109

European-Finnish (FIN) AF: 0.00639 AC: 259 AN: 40511

Middle Eastern (MID) AF: 0.00822 AC: 34 AN: 4136

European-Non Finnish (NFE) AF: 0.00414 AC: 3484 AN: 841902

Other (OTH) AF: 0.00453 AC: 209 AN: 46086

GnomAD4 genome AF: 0.00366 AC: 409 AN: 111598 Hom.: 1 Cov.: 22 AF XY: 0.00382 AC XY: 129 AN XY: 33766

African (AFR) AF: 0.000325 AC: 10 AN: 30726

American (AMR) AF: 0.00694 AC: 73 AN: 10513

Ashkenazi Jewish (ASJ) AF: 0.00680 AC: 18 AN: 2648

East Asian (EAS) AF: 0.00 AC: 0 AN: 3539

South Asian (SAS) AF: 0.00 AC: 0 AN: 2615

European-Finnish (FIN) AF: 0.00416 AC: 25 AN: 6008

Middle Eastern (MID) AF: 0.00459 AC: 1 AN: 218

European-Non Finnish (NFE) AF: 0.00495 AC: 263 AN: 53131

Other (OTH) AF: 0.00528 AC: 8 AN: 1514

Alfa AF: 0.00502 Hom.: 43

Bravo AF: 0.00428

EpiCase AF: 0.00704

EpiControl AF: 0.00630

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	2	not specified (2)
-	-	2	X-linked sideroblastic anemia 1 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	5.3
DANN	Benign	0.75
PhyloP100		0.22
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs150055592; hg19: chrX-55039959;