X-55009268-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 4P and 20B. PM1PM5BP4_StrongBP6_Very_StrongBS1BS2

The NM_000032.5(ALAS2):c.1676G>A(p.Arg559His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00248 in 1,203,790 control chromosomes in the GnomAD database, including 5 homozygotes. There are 932 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R559P) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0016 ( 1 hom., 51 hem., cov: 23)

Exomes 𝑓: 0.0026 ( 4 hom. 881 hem. )

Consequence

ALAS2
NM_000032.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.306

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 made for transcript

Verdict is Benign. Variant got -16 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_000032.5

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-55009268-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 214100.Status of the report is criteria_provided_single_submitter, 1 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.0092430115).

BP6

Variant X-55009268-C-T is Benign according to our data. Variant chrX-55009268-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 214090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-55009268-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00161 (178/110810) while in subpopulation NFE AF= 0.00242 (128/52909). AF 95% confidence interval is 0.00208. There are 1 homozygotes in gnomad4. There are 51 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 51 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALAS2	NM_000032.5 link	c.1676G>A	p.Arg559His	missense_variant	Exon 11 of 11	ENST00000650242.1	NP_000023.2	P22557-1
APEX2	NM_014481.4 link	c.*1833C>T		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.1676G>A	p.Arg559His	missense_variant	Exon 11 of 11		NM_000032.5	ENSP00000497236.1		P22557-1
APEX2	ENST00000374987.4 link	c.*1833C>T		downstream_gene_variant		1	NM_014481.4	ENSP00000364126.3		Q9UBZ4

Frequencies

GnomAD3 genomes

AF:

0.00161

AC:

178

AN:

110760

Hom.:

Cov.:

AF XY:

0.00155

AC XY:

AN XY:

32962

show subpopulations

Gnomad AFR

AF:

0.000230

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00163

Gnomad ASJ

AF:

0.00945

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00242

Gnomad OTH

AF:

0.000678

GnomAD3 exomes

AF:

0.00227

AC:

381

AN:

167537

Hom.:

AF XY:

0.00190

AC XY:

105

AN XY:

55189

show subpopulations

Gnomad AFR exome

AF:

0.000498

Gnomad AMR exome

AF:

0.00335

Gnomad ASJ exome

AF:

0.0114

Gnomad EAS exome

AF:

0.0000760

Gnomad SAS exome

AF:

0.0000586

Gnomad FIN exome

AF:

0.0000695

Gnomad NFE exome

AF:

0.00240

Gnomad OTH exome

AF:

0.00615

GnomAD4 exome

AF:

0.00257

AC:

2813

AN:

1092980

Hom.:

Cov.:

AF XY:

0.00245

AC XY:

881

AN XY:

359068

show subpopulations

Gnomad4 AFR exome

AF:

0.000341

Gnomad4 AMR exome

AF:

0.00323

Gnomad4 ASJ exome

AF:

0.0102

Gnomad4 EAS exome

AF:

0.0000332

Gnomad4 SAS exome

AF:

0.000132

Gnomad4 FIN exome

AF:

0.000150

Gnomad4 NFE exome

AF:

0.00281

Gnomad4 OTH exome

AF:

0.00257

GnomAD4 genome

AF:

0.00161

AC:

178

AN:

110810

Hom.:

Cov.:

AF XY:

0.00154

AC XY:

AN XY:

33022

show subpopulations

Gnomad4 AFR

AF:

0.000230

Gnomad4 AMR

AF:

0.00163

Gnomad4 ASJ

AF:

0.00945

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00242

Gnomad4 OTH

AF:

0.000669

Alfa

AF:

0.00249

Hom.:

102

Bravo

AF:

0.00162

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00173

AC:

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00312

AC:

ExAC

AF:

0.00222

AC:

269

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Oct 30, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 04, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 26562225, 21653323, 22995991, 15678587, 22740690, 30678654, 22269113, 20848343, 15678585, 16121195) -

not specified

Benign:1

May 22, 2017

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ALAS2-related disorder

Benign:1

Oct 12, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

X-linked sideroblastic anemia 1

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.44

CADD

Benign

0.37

DANN

Benign

0.89

DEOGEN2

Benign

0.20

.;T;T;.

FATHMM_MKL

Benign

0.056

LIST_S2

Uncertain

0.86

D;.;D;D

MetaRNN

Benign

0.0092

T;T;T;T

MetaSVM

Uncertain

-0.27

MutationAssessor

Benign

1.3

.;L;L;.

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.55

N;.;N;N

REVEL

Benign

0.27

Sift

Benign

0.59

T;.;T;T

Sift4G

Benign

0.34

T;.;T;T

Polyphen

0.0030

.;B;B;.

Vest4

0.13

MVP

0.75

MPC

0.62

ClinPred

0.0060

GERP RS

-3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.17

gMVP

0.52

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over