chrX-55023799-T-C

Variant names:

Variant summary

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

The NM_000032.5(ALAS2):c.373A>G(p.Ile125Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000048 in 1,208,599 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 12 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/23 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 0.00029 ( 0 hom., 7 hem., cov: 22)

Exomes 𝑓: 0.000024 ( 0 hom. 5 hem. )

Consequence

ALAS2
NM_000032.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 1.51

Publications

0 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 Gene-Disease associations (from GenCC):

X-linked erythropoietic protoporphyria
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
X-linked sideroblastic anemia 1
Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet

ALAS2 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=0.017120868).

BP6

Variant X-55023799-T-C is Benign according to our data. Variant chrX-55023799-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 434119.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000289 (32/110621) while in subpopulation AFR AF = 0.00105 (32/30342). AF 95% confidence interval is 0.000767. There are 0 homozygotes in GnomAd4. There are 7 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 7 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
ALAS2	NM_000032.5 link	c.373A>G	p.Ile125Val	missense_variant	Exon 4 of 11	ENST00000650242.1	NP_000023.2
ALAS2	NM_001037968.4 link	c.376+919A>G		intron_variant	Intron 4 of 10		NP_001033057.1
ALAS2	NM_001037967.4 link	c.304+919A>G		intron_variant	Intron 3 of 9		NP_001033056.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALAS2	ENST00000650242.1 link	c.373A>G	p.Ile125Val	missense_variant	Exon 4 of 11		NM_000032.5	ENSP00000497236.1

Frequencies

GnomAD3 genomes

AF:

0.000262

AC:

AN:

110572

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000958

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

GnomAD2 exomes

AF:

0.000115

AC:

AN:

182721

AF XY:

0.0000446

show subpopulations

Gnomad AFR exome

AF:

0.00160

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

AF:

0.0000237

AC:

AN:

1097978

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

363342

show subpopulations

African (AFR)

AF:

0.000871

AC:

AN:

26401

American (AMR)

AF:

0.00

AC:

AN:

35199

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19385

East Asian (EAS)

AF:

0.00

AC:

AN:

30204

South Asian (SAS)

AF:

0.00

AC:

AN:

54076

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40505

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4135

European-Non Finnish (NFE)

AF:

0.00000119

AC:

AN:

841986

Other (OTH)

AF:

0.0000434

AC:

AN:

46087

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

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:

0.000289

AC:

AN:

110621

Hom.:

Cov.:

AF XY:

0.000213

AC XY:

AN XY:

32917

show subpopulations

African (AFR)

AF:

0.00105

AC:

AN:

30342

American (AMR)

AF:

0.00

AC:

AN:

10348

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2627

East Asian (EAS)

AF:

0.00

AC:

AN:

3497

South Asian (SAS)

AF:

0.00

AC:

AN:

2583

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5886

Middle Eastern (MID)

AF:

0.00

AC:

AN:

215

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

52934

Other (OTH)

AF:

0.00

AC:

AN:

1509

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

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:

0.000104

Hom.:

Bravo

AF:

0.000268

ESP6500AA

AF:

0.00156

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000148

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 15, 2017

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Uncertain:1

Sep 09, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.373A>G (p.I125V) alteration is located in exon 4 (coding exon 3) of the ALAS2 gene. This alteration results from a A to G substitution at nucleotide position 373, causing the isoleucine (I) at amino acid position 125 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

X-linked sideroblastic anemia 1

Uncertain:1

Dec 19, 2023

Johns Hopkins Genomics, Johns Hopkins University

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This ALAS2 missense variant (rs143995220) is rare (<0.1%) in a large population dataset (gnomAD v4.0.0: 58/1208599 total alleles; 0.005%; 12 hemizygotes, no homozygotes). It has been reported in ClinVar (Variation ID 434119), but has not been reported in the literature, to our knowledge. Two bioinformatic tools queried predict that this substitution would be tolerated, and the isoleucine residue at this position is evolutionarily conserved across many of the species assessed. We consider the clinical significance of c.373A>G in ALAS2 to be uncertain at this time. -

not provided

Benign:1

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.36

CADD

Benign

6.0

(source)

DANN

Benign

0.55

DEOGEN2

Benign

0.20

T;T;.;.

FATHMM_MKL

Benign

0.083

LIST_S2

Benign

0.64

.;T;T;T

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.017

T;T;T;T

MetaSVM

Uncertain

-0.046

MutationAssessor

Benign

1.1

L;L;.;.

PhyloP100

1.5

PrimateAI

Benign

0.38

PROVEAN

Benign

0.090

.;N;.;.

REVEL

Benign

0.22

Sift

Benign

0.30

.;T;.;.

Sift4G

Benign

0.42

.;T;.;.

Polyphen

0.0

B;B;.;.

Vest4

0.063

MVP

0.58

MPC

0.42

ClinPred

0.027

GERP RS

4.2

Varity_R

0.086

gMVP

0.59

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.20

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.20

Position offset: -42

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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