rs137852300

Positions:

• chrX-55015583-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000032.5(ALAS2):​c.1163C>G​(p.Thr388Ser) 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: 10.0

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a binding_site in other chain (size 0) in uniprot entity HEM0_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant X-55015583-G-C is Pathogenic according to our data. Variant chrX-55015583-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 10469.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALAS2	NM_000032.5	c.1163C>G	p.Thr388Ser	missense_variant	8/11	ENST00000650242.1	NP_000023.2
ALAS2	NM_001037968.4	c.1124C>G	p.Thr375Ser	missense_variant	8/11		NP_001033057.1
ALAS2	NM_001037967.4	c.1052C>G	p.Thr351Ser	missense_variant	7/10		NP_001033056.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALAS2	ENST00000650242.1	c.1163C>G	p.Thr388Ser	missense_variant	8/11		NM_000032.5	ENSP00000497236	P1
ALAS2	ENST00000396198.7	c.1124C>G	p.Thr375Ser	missense_variant	8/11	5		ENSP00000379501
ALAS2	ENST00000335854.8	c.1052C>G	p.Thr351Ser	missense_variant	7/10	2		ENSP00000337131
ALAS2	ENST00000498636.1	c.455C>G	p.Thr152Ser	missense_variant	3/5	3		ENSP00000495662

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

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

Sep 21, 2005

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.61
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	.;D;D;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;.;D;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	3.3	.;M;M;.
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.8	D;.;D;D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D;.;D;D
Sift4G	Pathogenic	0.0	D;.;D;D
Polyphen		1.0	.;D;D;.
Vest4		0.89
MutPred		0.97		.;Loss of ubiquitination at K391 (P = 0.0962);Loss of ubiquitination at K391 (P = 0.0962);.;
MVP		0.99
MPC		1.3
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.92

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: rs137852300; hg19: chrX-55042016;