X-55009266-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 5P and 5B. PM1PM5PP3BS1_SupportingBS2

The NM_000032.5(ALAS2):c.1678C>T(p.Arg560Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000149 in 1,204,224 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R560H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.000016 ( 0 hom. 8 hem. )

Consequence

ALAS2
NM_000032.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.98

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: Uncertain_significance. The variant received 0 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 3 uncertain in NM_000032.5

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.757

BS1

Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.0000155 (17/1093260) while in subpopulation SAS AF = 0.00017 (9/52961). AF 95% confidence interval is 0.0000886. There are 0 homozygotes in GnomAdExome4. There are 8 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position FAILED quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Hemizygotes in GnomAdExome4 at 8 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALAS2	NM_000032.5 link	c.1678C>T	p.Arg560Cys	missense_variant	Exon 11 of 11	ENST00000650242.1	NP_000023.2	P22557-1
APEX2	NM_014481.4 link	c.*1831G>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.1678C>T	p.Arg560Cys	missense_variant	Exon 11 of 11		NM_000032.5	ENSP00000497236.1		P22557-1
APEX2	ENST00000374987.4 link	c.*1831G>A		downstream_gene_variant		1	NM_014481.4	ENSP00000364126.3		Q9UBZ4

Frequencies

GnomAD3 genomes

AF:

0.00000901

AC:

AN:

110964

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000329

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:

0.0000417

AC:

AN:

168020

AF XY:

0.0000542

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000136

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000155

AC:

AN:

1093260

Hom.:

Cov.:

AF XY:

0.0000223

AC XY:

AN XY:

359256

show subpopulations

Gnomad4 AFR exome

AF:

0.00

AC:

AN:

26352

Gnomad4 AMR exome

AF:

0.00

AC:

AN:

34661

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

19284

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

30107

Gnomad4 SAS exome

AF:

0.000170

AC:

AN:

52961

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

40144

Gnomad4 NFE exome

AF:

0.00000953

AC:

AN:

839722

Gnomad4 Remaining exome

AF:

0.00

AC:

AN:

45902

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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:

0.00000901

AC:

AN:

110964

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33150

show subpopulations

Gnomad4 AFR

AF:

0.0000329

AC:

0.0000328515

AN:

0.0000328515

Gnomad4 AMR

AF:

0.00

AC:

AN:

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.00

AC:

AN:

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

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:

0.00

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Nov 06, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 560 of the ALAS2 protein (p.Arg560Cys). This variant is present in population databases (rs778388971, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with ALAS2-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ALAS2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.43

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.66

.;D;D;.

FATHMM_MKL

Uncertain

0.87

LIST_S2

Pathogenic

0.98

D;.;D;D

M_CAP

Pathogenic

0.56

MetaRNN

Pathogenic

0.76

D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.1

.;M;M;.

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-3.7

D;.;D;D

REVEL

Pathogenic

0.84

Sift

Uncertain

0.0010

D;.;D;D

Sift4G

Uncertain

0.0020

D;.;D;D

Polyphen

1.0

.;D;D;.

Vest4

0.39

MutPred

0.62

.;Gain of helix (P = 0.062);Gain of helix (P = 0.062);.;

MVP

0.97

MPC

1.5

ClinPred

0.64

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.91

gMVP

0.89

Mutation Taster

=89/11

polymorphism

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