X-55009202-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000032.5(ALAS2):c.1742A>G(p.Gln581Arg) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: ALAS2 NM_000032.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.32

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35268456).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALAS2	NM_000032.5	c.1742A>G	p.Gln581Arg	missense_variant	11/11	ENST00000650242.1
ALAS2	NM_001037968.4	c.1703A>G	p.Gln568Arg	missense_variant	11/11
ALAS2	NM_001037967.4	c.1631A>G	p.Gln544Arg	missense_variant	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALAS2	ENST00000650242.1	c.1742A>G	p.Gln581Arg	missense_variant	11/11		NM_000032.5	P1
ALAS2	ENST00000396198.7	c.1703A>G	p.Gln568Arg	missense_variant	11/11	5
ALAS2	ENST00000335854.8	c.1631A>G	p.Gln544Arg	missense_variant	10/10	2
ALAS2	ENST00000498636.1	c.*40A>G		3_prime_UTR_variant	5/5	3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 10, 2023

ClinVar contains an entry for this variant (Variation ID: 1351081). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ALAS2 protein function. This variant has not been reported in the literature in individuals affected with ALAS2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 581 of the ALAS2 protein (p.Gln581Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.0079	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	20
Dann	Uncertain	0.98
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.78	T;.;T;T
M_CAP	Pathogenic	0.64	D
MetaRNN	Benign	0.35	T;T;T;T
MetaSVM	Uncertain	0.39	D
MutationTaster	Benign	0.91	D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.1	N;.;N;N
REVEL	Uncertain	0.35
Sift	Benign	0.13	T;.;T;T
Sift4G	Benign	0.15	T;.;T;T
Polyphen		0.074	.;B;B;.
Vest4		0.22
MutPred		0.25		.;Loss of loop (P = 0.0235);Loss of loop (P = 0.0235);.;
MVP		0.86
MPC		0.54
ClinPred		0.29	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.87

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-55035635;