X-55009249-C-G

Variant names:

• chrX-55009249-C-G
• rs149747514
• NM_000032.5:c.1695G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4 BP6

The NM_000032.5(ALAS2):​c.1695G>C​(p.Glu565Asp) 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. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E565Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: ALAS2 NM_000032.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.779

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]

APEX2 (HGNC:17889): (apurinic/apyrimidinic endodeoxyribonuclease 2) Apurinic/apyrimidinic (AP) sites occur frequently in DNA molecules by spontaneous hydrolysis, by DNA damaging agents or by DNA glycosylases that remove specific abnormal bases. AP sites are pre-mutagenic lesions that can prevent normal DNA replication so the cell contains systems to identify and repair such sites. Class II AP endonucleases cleave the phosphodiester backbone 5' to the AP site. This gene encodes a protein shown to have a weak class II AP endonuclease activity. Most of the encoded protein is located in the nucleus but some is also present in mitochondria. This protein may play an important role in both nuclear and mitochondrial base excision repair. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Nov 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 3 uncertain in NM_000032.5
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26509172).
• BP6: Variant X-55009249-C-G is Benign according to our data. Variant chrX-55009249-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2634710.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALAS2	NM_000032.5	c.1695G>C	p.Glu565Asp	missense_variant	Exon 11 of 11	ENST00000650242.1	NP_000023.2
APEX2	NM_014481.4	c.*1814C>G		downstream_gene_variant		ENST00000374987.4	NP_055296.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALAS2	ENST00000650242.1	c.1695G>C	p.Glu565Asp	missense_variant	Exon 11 of 11		NM_000032.5	ENSP00000497236.1
APEX2	ENST00000374987.4	c.*1814C>G		downstream_gene_variant		1	NM_014481.4	ENSP00000364126.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.00000585 AC: 1 AN: 170826 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 57204

Gnomad AFR exome AF: 0.0000815

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000378

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.00 AC: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

ALAS2-related disorder Uncertain:1

Apr 20, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ALAS2 c.1695G>C variant is predicted to result in the amino acid substitution p.Glu565Asp. To our knowledge, this variant has not been reported in patients with ALAS2-related disorder. However, in a functional analysis, this variant was found to result in a small gain of function in enzymatic activity (Tchaikovskii et al. 2019. PubMed ID: 30678654). This variant is reported in 0.0081% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/X-55035682-C-G). Of note, a different variant impacting the same amino acid residue (p.Glu565Lys) has been reported in a patient with sideroblastic anemia onset in the third decade of life (Liu et al. 2013. PubMed ID: 24323989). At this time, the clinical significance of the c.1695G>C (p.Glu565Asp) variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided Benign:1

May 15, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	.;T;T;.
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.83	T;.;T;T
M_CAP	Pathogenic	0.60	D
MetaRNN	Benign	0.27	T;T;T;T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	-0.28	.;N;N;.
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.51	N;.;N;N
REVEL	Uncertain	0.32
Sift	Benign	0.32	T;.;T;T
Sift4G	Benign	0.38	T;.;T;T
Polyphen		0.0010	.;B;B;.
Vest4		0.12
MutPred		0.50		.;Gain of relative solvent accessibility (P = 0.0479);Gain of relative solvent accessibility (P = 0.0479);.;
MVP		0.72
MPC		0.45
ClinPred		0.24	T
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.28
gMVP		0.51

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: rs149747514; hg19: chrX-55035682;