rs143995220

Positions:

chrX-55023799-T-C

Variant summary

Our verdict is Benign. Variant got -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. 14/22 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:2B:1

Conservation

PhyloP100: 1.51

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 434119.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=2}.

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 male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 7 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ALAS2	NM_000032.5 linkuse as main transcript	c.373A>G	p.Ile125Val	missense_variant	4/11	ENST00000650242.1	NP_000023.2
ALAS2	NM_001037967.4 linkuse as main transcript	c.304+919A>G		intron_variant			NP_001033056.1
ALAS2	NM_001037968.4 linkuse as main transcript	c.376+919A>G		intron_variant			NP_001033057.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALAS2	ENST00000650242.1 linkuse as main transcript	c.373A>G	p.Ile125Val	missense_variant	4/11		NM_000032.5	ENSP00000497236	P1	P22557-1

Frequencies

GnomAD3 genomes

AF:

0.000262

AC:

AN:

110572

Hom.:

Cov.:

AF XY:

0.000122

AC XY:

AN XY:

32858

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

GnomAD3 exomes

AF:

0.000115

AC:

AN:

182721

Hom.:

AF XY:

0.0000446

AC XY:

AN XY:

67247

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 SAS 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

Gnomad4 AFR exome

AF:

0.000871

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000119

Gnomad4 OTH exome

AF:

0.0000434

GnomAD4 genome

AF:

0.000289

AC:

AN:

110621

Hom.:

Cov.:

AF XY:

0.000213

AC XY:

AN XY:

32917

show subpopulations

Gnomad4 AFR

AF:

0.00105

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000178

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:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 15, 2017

- -

X-linked sideroblastic anemia 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Johns Hopkins Genomics, Johns Hopkins University

Dec 19, 2023

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 25, 2023

- -

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

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;.;.

MutationTaster

Benign

1.0

N;N;N

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

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

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