X-55009248-G-A

Variant summary

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

The NM_000032.5(ALAS2):c.1696C>T(p.Leu566Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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: 3.85

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 3 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.1696C>T	p.Leu566Phe	missense_variant	11/11	ENST00000650242.1
ALAS2	NM_001037968.4	c.1657C>T	p.Leu553Phe	missense_variant	11/11
ALAS2	NM_001037967.4	c.1585C>T	p.Leu529Phe	missense_variant	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALAS2	ENST00000650242.1	c.1696C>T	p.Leu566Phe	missense_variant	11/11		NM_000032.5	P1
ALAS2	ENST00000396198.7	c.1657C>T	p.Leu553Phe	missense_variant	11/11	5
ALAS2	ENST00000335854.8	c.1585C>T	p.Leu529Phe	missense_variant	10/10	2
ALAS2	ENST00000498636.1	c.825C>T	p.Ser275=	synonymous_variant	5/5	3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 29, 2023

The c.1696C>T (p.L566F) alteration is located in exon 11 (coding exon 10) of the ALAS2 gene. This alteration results from a C to T substitution at nucleotide position 1696, causing the leucine (L) at amino acid position 566 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
Cadd	Uncertain	25
Dann	Uncertain	1.0
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.89	D;.;D;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Uncertain	0.56	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.4	N;.;N;N
REVEL	Uncertain	0.64
Sift	Uncertain	0.0070	D;.;D;D
Sift4G	Uncertain	0.057	T;.;T;T
Polyphen		0.97	.;D;D;.
Vest4		0.41
MutPred		0.29		.;Loss of loop (P = 0.0986);Loss of loop (P = 0.0986);.;
MVP		0.96
MPC		1.1
ClinPred		0.93	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.80
gMVP		0.68

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: rs1241366449; hg19: chrX-55035681;