X-55009251-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000032.5(ALAS2):c.1693G>C(p.Glu565Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E565D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 22)
• Consequence: ALAS2 NM_000032.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.17

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 4 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALAS2	NM_000032.5	c.1693G>C	p.Glu565Gln	missense_variant	11/11	ENST00000650242.1
ALAS2	NM_001037968.4	c.1654G>C	p.Glu552Gln	missense_variant	11/11
ALAS2	NM_001037967.4	c.1582G>C	p.Glu528Gln	missense_variant	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALAS2	ENST00000650242.1	c.1693G>C	p.Glu565Gln	missense_variant	11/11		NM_000032.5	P1
ALAS2	ENST00000396198.7	c.1654G>C	p.Glu552Gln	missense_variant	11/11	5
ALAS2	ENST00000335854.8	c.1582G>C	p.Glu528Gln	missense_variant	10/10	2
ALAS2	ENST00000498636.1	c.822G>C	p.Leu274Phe	missense_variant	5/5	3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

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

GeneDx

Feb 07, 2017

The E565Q variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The E565Q variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The E565Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Benign	-0.19
Cadd	Benign	19
Dann	Uncertain	0.99
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	D;.;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.48	T;T;T;T
MetaSVM	Pathogenic	0.80	D
MutationTaster	Benign	0.74	D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.5	N;.;N;N
REVEL	Uncertain	0.47
Sift	Uncertain	0.0060	D;.;D;D
Sift4G	Uncertain	0.014	D;.;D;D
Polyphen		0.57	.;P;P;.
Vest4		0.39
MutPred		0.53		.;Loss of loop (P = 0.0986);Loss of loop (P = 0.0986);.;
MVP		0.95
MPC		0.52
ClinPred		0.92	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.63
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1057524863; hg19: chrX-55035684;