rs139596860

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000032.5(ALAS2):c.1757A>T(p.Tyr586Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000399 in 1,205,917 control chromosomes in the GnomAD database, including 1 homozygotes. There are 141 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0020 ( 0 hom., 67 hem., cov: 23)

Exomes 𝑓: 0.00024 ( 1 hom. 74 hem. )

Consequence

ALAS2
NM_000032.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:2O:1

Conservation

PhyloP100: 0.262

Publications

8 publications found

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]

ALAS2 links:

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]

APEX2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0068839192).

BP6

Variant X-55009187-T-A is Benign according to our data. Variant chrX-55009187-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 40978.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00195 (217/111123) while in subpopulation AFR AF = 0.00668 (204/30557). AF 95% confidence interval is 0.00593. There are 0 homozygotes in GnomAd4. There are 67 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 67 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALAS2	NM_000032.5 link	c.1757A>T	p.Tyr586Phe	missense_variant	Exon 11 of 11	ENST00000650242.1	NP_000023.2	P22557-1
APEX2	NM_014481.4 link	c.*1752T>A		downstream_gene_variant		ENST00000374987.4	NP_055296.2	Q9UBZ4E5KN95

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALAS2	ENST00000650242.1 link	c.1757A>T	p.Tyr586Phe	missense_variant	Exon 11 of 11		NM_000032.5	ENSP00000497236.1		P22557-1
APEX2	ENST00000374987.4 link	c.*1752T>A		downstream_gene_variant		1	NM_014481.4	ENSP00000364126.3		Q9UBZ4

Frequencies

GnomAD3 genomes

AF:

0.00185

AC:

206

AN:

111072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00633

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00114

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000672

GnomAD2 exomes

AF:

0.000563

AC:

AN:

172239

AF XY:

0.000310

show subpopulations

Gnomad AFR exome

AF:

0.00645

Gnomad AMR exome

AF:

0.000564

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000131

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000241

AC:

264

AN:

1094794

Hom.:

Cov.:

AF XY:

0.000205

AC XY:

AN XY:

360564

show subpopulations

African (AFR)

AF:

0.00671

AC:

177

AN:

26380

American (AMR)

AF:

0.000459

AC:

AN:

34868

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19309

East Asian (EAS)

AF:

0.00

AC:

AN:

30139

South Asian (SAS)

AF:

0.000113

AC:

AN:

53163

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40276

Middle Eastern (MID)

AF:

0.00170

AC:

AN:

4128

European-Non Finnish (NFE)

AF:

0.0000119

AC:

AN:

840553

Other (OTH)

AF:

0.00104

AC:

AN:

45978

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00195

AC:

217

AN:

111123

Hom.:

Cov.:

AF XY:

0.00201

AC XY:

AN XY:

33359

show subpopulations

African (AFR)

AF:

0.00668

AC:

204

AN:

30557

American (AMR)

AF:

0.00114

AC:

AN:

10496

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2638

East Asian (EAS)

AF:

0.00

AC:

AN:

3522

South Asian (SAS)

AF:

0.00

AC:

AN:

2585

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5988

Middle Eastern (MID)

AF:

0.00

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

52936

Other (OTH)

AF:

0.000664

AC:

AN:

1506

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000435

Hom.:

Bravo

AF:

0.00210

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00808

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000717

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:2Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:1

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 05, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 30, 2016

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The Y586F variant has previously been reported as heterozygous in a single female patient with moderate congenital erythropoietic porphyria (To-Figueras et al., 2011). Functional analysis of Y586F found that it is assocaited with only a mild gain of function in vitro (To-Figueras et al., 2011). However, the NHLBI Exome Sequencing Project reports Y586F was observed in 31/3835 alleles from individuals of African-American background, indicating it may be a rare, benign variant in this population. The Y586F variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. In silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

X-linked sideroblastic anemia 1

Uncertain:1

May 28, 2019

Mendelics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Developmental and epileptic encephalopathy, 36

Benign:1

Jun 27, 2024

Dr.Nikuei Genetic Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

X-linked erythropoietic protoporphyria

Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.18

CADD

Benign

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.28

.;T;T;.

FATHMM_MKL

Benign

0.57

LIST_S2

Benign

0.81

T;.;T;T

M_CAP

Uncertain

0.24

MetaRNN

Benign

0.0069

T;T;T;T

MetaSVM

Uncertain

-0.093

MutationAssessor

Benign

0.46

.;N;N;.

PhyloP100

0.26

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-0.89

N;.;N;N

REVEL

Benign

0.28

Sift

Benign

0.085

T;.;T;T

Sift4G

Benign

0.20

T;.;T;T

Polyphen

0.016

.;B;B;.

Vest4

0.15

MVP

0.83

MPC

0.45

ClinPred

0.0035

GERP RS

4.2

Varity_R

0.17

gMVP

0.67

Mutation Taster

=98/2

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over