X-55009245-T-C

Position:

• chrX-55009245-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3 PP5_Moderate

The NM_000032.5(ALAS2):​c.1699A>G​(p.Met567Val) variant causes a missense change. 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 (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: ALAS2 NM_000032.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.25

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 7 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 4 uncertain in NM_000032.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.807
• PP5: Variant X-55009245-T-C is Pathogenic according to our data. Variant chrX-55009245-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 214104.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALAS2	NM_000032.5	c.1699A>G	p.Met567Val	missense_variant	11/11	ENST00000650242.1
ALAS2	NM_001037968.4	c.1660A>G	p.Met554Val	missense_variant	11/11
ALAS2	NM_001037967.4	c.1588A>G	p.Met530Val	missense_variant	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALAS2	ENST00000650242.1	c.1699A>G	p.Met567Val	missense_variant	11/11		NM_000032.5	P1
ALAS2	ENST00000396198.7	c.1660A>G	p.Met554Val	missense_variant	11/11	5
ALAS2	ENST00000335854.8	c.1588A>G	p.Met530Val	missense_variant	10/10	2
ALAS2	ENST00000498636.1	c.828A>G	p.Ser276=	synonymous_variant	5/5	3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 03, 2014

p.Met567Val (ATG>GTG): c.1699 A>G in exon 11 of the ALAS2 gene (NM_000032.4). The M567V missense mutation in the ALAS2 gene has been reported previously in a patient with X-linked hereditary sideroblastic anemia (Bishop et al., 2012). Functional studies suggest that the mutation interferes with binding between ALAS2 and succinyl-CoA synthase and disrupts the complex (Bishop et al., 2012). This complex is hypothesized to play an important role in in vivo heme biosynthesis. This result is expected to be consistent with a diagnosis of X-linked hereditary sideroblastic anemia. The variant is found in MITONUC-MITOP panel(s). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.67
CADD	Benign	23
DANN	Uncertain	0.99
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.89	D;.;D;D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.81	D;D;D;D
MetaSVM	Pathogenic	0.98	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-2.2	N;.;N;N
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0040	D;.;D;D
Sift4G	Uncertain	0.010	D;.;D;D
Polyphen		0.77	.;P;P;.
Vest4		0.81
MutPred		0.33		.;Gain of loop (P = 0.0195);Gain of loop (P = 0.0195);.;
MVP		1.0
MPC		1.1
ClinPred		0.94	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.84

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: rs863223906; hg19: chrX-55035678;