X-55014830-G-A

Variant names:

• chrX-55014830-G-A
• rs137852311
• NM_000032.5:c.1354C>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000032.5(ALAS2):​c.1354C>T​(p.Arg452Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000183 in 1,090,557 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples 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: not found (cov: 24)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
• Consequence: ALAS2 NM_000032.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 6.32
• Publications: 18 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: 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: Pathogenic. The variant received 16 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, 0.974
• PP5: Variant X-55014830-G-A is Pathogenic according to our data. Variant chrX-55014830-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 10485.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALAS2	NM_000032.5	MANE Select	c.1354C>T	p.Arg452Cys	missense	Exon 9 of 11	NP_000023.2	P22557-1
	ALAS2	NM_001037968.4		c.1315C>T	p.Arg439Cys	missense	Exon 9 of 11	NP_001033057.1	P22557-4
	ALAS2	NM_001037967.4		c.1243C>T	p.Arg415Cys	missense	Exon 8 of 10	NP_001033056.1	P22557-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALAS2	ENST00000650242.1	MANE Select	c.1354C>T	p.Arg452Cys	missense	Exon 9 of 11	ENSP00000497236.1	P22557-1
	ALAS2	ENST00000396198.7	TSL:5	c.1315C>T	p.Arg439Cys	missense	Exon 9 of 11	ENSP00000379501.3	P22557-4
	ALAS2	ENST00000335854.8	TSL:2	c.1243C>T	p.Arg415Cys	missense	Exon 8 of 10	ENSP00000337131.4	P22557-2

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.00000183 AC: 2 AN: 1090557 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 357139

African (AFR) AF: 0.00 AC: 0 AN: 26256

American (AMR) AF: 0.00 AC: 0 AN: 34408

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19215

East Asian (EAS) AF: 0.00 AC: 0 AN: 29850

South Asian (SAS) AF: 0.00 AC: 0 AN: 52699

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40009

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4029

European-Non Finnish (NFE) AF: 0.00000239 AC: 2 AN: 838328

Other (OTH) AF: 0.00 AC: 0 AN: 45763

GnomAD4 genome Cov.: 24

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
2	-	-	X-linked sideroblastic anemia 1 (2)
1	-	-	ALAS2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		6.3
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-4.3	D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.013	D
Polyphen		1.0	D
Vest4		0.69
MutPred		0.87		Loss of disorder (P = 0.0145)
MVP		0.99
MPC		1.6
ClinPred		0.99	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.85
gMVP		0.94
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs137852311; hg19: chrX-55041263;