X-55009268-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM1 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R559H) has been classified as Likely benign.

• 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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_000032.5
• 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/exons	MANE	UniProt
ALAS2	NM_000032.5	c.1676G>C	p.Arg559Pro	missense_variant	11/11	ENST00000650242.1
ALAS2	NM_001037968.4	c.1637G>C	p.Arg546Pro	missense_variant	11/11
ALAS2	NM_001037967.4	c.1565G>C	p.Arg522Pro	missense_variant	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALAS2	ENST00000650242.1	c.1676G>C	p.Arg559Pro	missense_variant	11/11		NM_000032.5	P1
ALAS2	ENST00000396198.7	c.1637G>C	p.Arg546Pro	missense_variant	11/11	5
ALAS2	ENST00000335854.8	c.1565G>C	p.Arg522Pro	missense_variant	10/10	2
ALAS2	ENST00000498636.1	c.805G>C	p.Ala269Pro	missense_variant	5/5	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

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 08, 2013

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
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
MutationTaster	Benign	1.0	N;N;N
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;