X-55009242-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_000032.5(ALAS2):c.1702A>G(p.Ser568Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 22)
• Consequence: ALAS2 NM_000032.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.02

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.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.896
• PP5: Variant X-55009242-T-C is Pathogenic according to our data. Variant chrX-55009242-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 10476.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALAS2	NM_000032.5	c.1702A>G	p.Ser568Gly	missense_variant	11/11	ENST00000650242.1
ALAS2	NM_001037968.4	c.1663A>G	p.Ser555Gly	missense_variant	11/11
ALAS2	NM_001037967.4	c.1591A>G	p.Ser531Gly	missense_variant	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALAS2	ENST00000650242.1	c.1702A>G	p.Ser568Gly	missense_variant	11/11		NM_000032.5	P1
ALAS2	ENST00000498636.1	c.831A>G	p.Ter277TrpextTer26	stop_lost	5/5	3
ALAS2	ENST00000396198.7	c.1663A>G	p.Ser555Gly	missense_variant	11/11	5
ALAS2	ENST00000335854.8	c.1591A>G	p.Ser531Gly	missense_variant	10/10	2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

Alfa AF: 0.00209 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

X-linked sideroblastic anemia 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 1999

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.63
Cadd	Uncertain	25
Dann	Uncertain	1.0
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D;.;D;D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.90	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-2.5	N;.;N;N
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0020	D;.;D;D
Sift4G	Uncertain	0.0030	D;.;D;D
Polyphen		1.0	.;D;D;.
Vest4		0.78
MutPred		0.63		.;Loss of helix (P = 0.028);Loss of helix (P = 0.028);.;
MVP		1.0
MPC		0.98
ClinPred		0.95	D
GERP RS		5.4
Varity_R		0.81
gMVP		0.72

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: rs137852306; hg19: chrX-55035675;