X-55009268-C-G

Variant names:

• chrX-55009268-C-G
• rs145704441
• NM_000032.5:c.1676G>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PP5_Moderate BP4

The NM_000032.5(ALAS2):​c.1676G>C​(p.Arg559Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: ALAS2 NM_000032.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.306

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]

APEX2 (HGNC:17889): (apurinic/apyrimidinic endodeoxyribonuclease 2) Apurinic/apyrimidinic (AP) sites occur frequently in DNA molecules by spontaneous hydrolysis, by DNA damaging agents or by DNA glycosylases that remove specific abnormal bases. AP sites are pre-mutagenic lesions that can prevent normal DNA replication so the cell contains systems to identify and repair such sites. Class II AP endonucleases cleave the phosphodiester backbone 5' to the AP site. This gene encodes a protein shown to have a weak class II AP endonuclease activity. Most of the encoded protein is located in the nucleus but some is also present in mitochondria. This protein may play an important role in both nuclear and mitochondrial base excision repair. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Nov 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-55009268-C-G is Pathogenic according to our data. Variant chrX-55009268-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 214100.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3853199). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALAS2	NM_000032.5	c.1676G>C	p.Arg559Pro	missense_variant	Exon 11 of 11	ENST00000650242.1	NP_000023.2
APEX2	NM_014481.4	c.*1833C>G		downstream_gene_variant		ENST00000374987.4	NP_055296.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALAS2	ENST00000650242.1	c.1676G>C	p.Arg559Pro	missense_variant	Exon 11 of 11		NM_000032.5	ENSP00000497236.1
APEX2	ENST00000374987.4	c.*1833C>G		downstream_gene_variant		1	NM_014481.4	ENSP00000364126.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Jan 08, 2013

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Arg559Pro (CGC>CCC): c.1676 G>C in exon 11 of the ALAS2 gene (NM_000032.4). The R559P missense change likely associated with hereditary X-linked sideroblastic anemia was identified in the ALAS2 gene. It has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The amino acid change is non-conservative in that a positively charged Arginine residue is replaced by an uncharged Proline residue with a unique ring structure. This change occurs at a position in the ALAS2 protein where a basic amino acid is conserved in mammals. Furthermore, most in-silico analysis models predict that R559P is damaging to the ALAS2 protein. Therefore, R559P is a strong candidate for a disease-causing mutation, however the possibility that it is a benign variant cannot be excluded. The variant is found in MITONUC-MITOP panel(s). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Uncertain	0.063	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	7.9
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	.;T;T;.
FATHMM_MKL	Benign	0.25	N
LIST_S2	Uncertain	0.95	D;.;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.39	T;T;T;T
MetaSVM	Uncertain	0.44	D
MutationAssessor	Uncertain	2.0	.;M;M;.
PrimateAI	Benign	0.22	T
PROVEAN	Uncertain	-2.4	N;.;N;N
REVEL	Uncertain	0.43
Sift	Uncertain	0.018	D;.;D;D
Sift4G	Uncertain	0.023	D;.;D;D
Polyphen		0.74	.;P;P;.
Vest4		0.40
MutPred		0.63		.;Loss of helix (P = 0.079);Loss of helix (P = 0.079);.;
MVP		0.78
MPC		1.1
ClinPred		0.87	D
GERP RS		-3.5
Varity_R		0.89
gMVP		0.90

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

Publications

LitVar

Other links and lift over

dbSNP: rs145704441; hg19: chrX-55035701;