X-55009187-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_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.

Frequency

Genomes: š‘“ 0.0000090 ( 0 hom., 1 hem., cov: 23)

Consequence

ALAS2
NM_000032.5 missense

Scores

1
4
12

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.262
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

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

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ALAS2NM_000032.5 linkc.1757A>C p.Tyr586Ser missense_variant Exon 11 of 11 ENST00000650242.1 NP_000023.2 P22557-1
APEX2NM_014481.4 linkc.*1752T>G downstream_gene_variant ENST00000374987.4 NP_055296.2 Q9UBZ4E5KN95

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ALAS2ENST00000650242.1 linkc.1757A>C p.Tyr586Ser missense_variant Exon 11 of 11 NM_000032.5 ENSP00000497236.1 P22557-1
APEX2ENST00000374987.4 linkc.*1752T>G downstream_gene_variant 1 NM_014481.4 ENSP00000364126.3 Q9UBZ4

Frequencies

GnomAD3 genomes
AF:
0.00000900
AC:
1
AN:
111073
Hom.:
0
Cov.:
23
AF XY:
0.0000300
AC XY:
1
AN XY:
33299
show subpopulations
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
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000385
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;T;.
FATHMM_MKL
Benign
0.40
N
LIST_S2
Benign
0.82
T;.;T;T
M_CAP
Pathogenic
0.30
D
MetaRNN
Benign
0.12
T;T;T;T
MetaSVM
Uncertain
0.27
D
MutationAssessor
Benign
0.26
.;N;N;.
PrimateAI
Uncertain
0.59
T
PROVEAN
Benign
-0.51
N;.;N;N
REVEL
Uncertain
0.34
Sift
Benign
0.10
T;.;T;T
Sift4G
Benign
0.25
T;.;T;T
Polyphen
0.065
.;B;B;.
Vest4
0.21
MutPred
0.25
.;Gain of relative solvent accessibility (P = 0.005);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

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs139596860; hg19: chrX-55035620; API