chrX-55009187-T-G

Variant names:

• chrX-55009187-T-G
• rs139596860
• NM_000032.5:c.1757A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000032.5(ALAS2):​c.1757A>C​(p.Tyr586Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000009 in 111,073 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y586F) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.0000090 (0 hom., 1 hem., cov: 23)
• Consequence: ALAS2 NM_000032.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.262
• Publications: 8 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11588526).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALAS2	NM_000032.5	MANE Select	c.1757A>C	p.Tyr586Ser	missense	Exon 11 of 11	NP_000023.2
	ALAS2	NM_001037968.4		c.1718A>C	p.Tyr573Ser	missense	Exon 11 of 11	NP_001033057.1
	ALAS2	NM_001037967.4		c.1646A>C	p.Tyr549Ser	missense	Exon 10 of 10	NP_001033056.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALAS2	ENST00000650242.1	MANE Select	c.1757A>C	p.Tyr586Ser	missense	Exon 11 of 11	ENSP00000497236.1
	ALAS2	ENST00000396198.7	TSL:5	c.1718A>C	p.Tyr573Ser	missense	Exon 11 of 11	ENSP00000379501.3
	ALAS2	ENST00000335854.8	TSL:2	c.1646A>C	p.Tyr549Ser	missense	Exon 10 of 10	ENSP00000337131.4

Frequencies

GnomAD3 genomes AF: 0.00000900 AC: 1 AN: 111073 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000385

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000900 AC: 1 AN: 111073 Hom.: 0 Cov.: 23 AF XY: 0.0000300 AC XY: 1 AN XY: 33299

African (AFR) AF: 0.00 AC: 0 AN: 30490

American (AMR) AF: 0.00 AC: 0 AN: 10483

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2638

East Asian (EAS) AF: 0.00 AC: 0 AN: 3533

South Asian (SAS) AF: 0.000385 AC: 1 AN: 2595

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5988

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52943

Other (OTH) AF: 0.00 AC: 0 AN: 1487

Alfa AF: 0.00 Hom.: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	17
DANN	Benign	0.86
DEOGEN2	Benign	0.20	T
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.12	T
MetaSVM	Uncertain	0.27	D
MutationAssessor	Benign	0.26	N
PhyloP100		0.26
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.51	N
REVEL	Uncertain	0.34
Sift	Benign	0.10	T
Sift4G	Benign	0.25	T
Polyphen		0.065	B
Vest4		0.21
MutPred		0.25		Gain of relative solvent accessibility (P = 0.005)
MVP		0.78
MPC		0.71
ClinPred		0.052	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.88
Mutation Taster		=78/22	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: rs139596860; hg19: chrX-55035620;