rs149747514

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chrX-55009249-C-G
• chrX-55009249-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 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. 12/21 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
• Publications: 2 publications found

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

Our verdict: Uncertain_significance. The variant received 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, 5 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 VariationId is 2634710.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000032.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALAS2	NM_000032.5	MANE Select	c.1695G>C	p.Glu565Asp	missense	Exon 11 of 11	NP_000023.2	P22557-1
	ALAS2	NM_001037968.4		c.1656G>C	p.Glu552Asp	missense	Exon 11 of 11	NP_001033057.1	P22557-4
	ALAS2	NM_001037967.4		c.1584G>C	p.Glu528Asp	missense	Exon 10 of 10	NP_001033056.1	P22557-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALAS2	ENST00000650242.1	MANE Select	c.1695G>C	p.Glu565Asp	missense	Exon 11 of 11	ENSP00000497236.1	P22557-1
	ALAS2	ENST00000396198.7	TSL:5	c.1656G>C	p.Glu552Asp	missense	Exon 11 of 11	ENSP00000379501.3	P22557-4
	ALAS2	ENST00000335854.8	TSL:2	c.1584G>C	p.Glu528Asp	missense	Exon 10 of 10	ENSP00000337131.4	P22557-2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.00000585 AC: 1 AN: 170826 AF XY: 0.00

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 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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.00 AC: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	ALAS2-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.83	T
M_CAP	Pathogenic	0.60	D
MetaRNN	Benign	0.27	T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	-0.28	N
PhyloP100		0.78
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.51	N
REVEL	Uncertain	0.32
Sift	Benign	0.32	T
Sift4G	Benign	0.38	T
Polyphen		0.0010	B
Vest4		0.12
MutPred		0.50		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
Mutation Taster		=71/28	polymorphism

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

Other links and lift over

dbSNP: rs149747514; hg19: chrX-55035682;