X-55009212-T-G

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_000032.5(ALAS2):c.1732A>C(p.Met578Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000497 in 1,206,224 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0000046 ( 0 hom. 2 hem. )

Consequence

ALAS2
NM_000032.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.99

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 Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.23195839).

BS2

High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALAS2	NM_000032.5 link	c.1732A>C	p.Met578Leu	missense_variant	Exon 11 of 11	ENST00000650242.1	NP_000023.2	P22557-1
APEX2	NM_014481.4 link	c.*1777T>G		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.1732A>C	p.Met578Leu	missense_variant	Exon 11 of 11		NM_000032.5	ENSP00000497236.1		P22557-1
APEX2	ENST00000374987.4 link	c.*1777T>G		downstream_gene_variant		1	NM_014481.4	ENSP00000364126.3		Q9UBZ4

Frequencies

GnomAD3 genomes

AF:

0.00000901

AC:

AN:

110940

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33108

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000955

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:

0.0000230

AC:

AN:

173696

Hom.:

AF XY:

0.0000169

AC XY:

AN XY:

59278

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000150

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:

0.00000457

AC:

AN:

1095284

Hom.:

Cov.:

AF XY:

0.00000554

AC XY:

AN XY:

360888

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000143

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000901

AC:

AN:

110940

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33108

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000955

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

Bravo

AF:

0.0000151

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Jan 16, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 578 of the ALAS2 protein (p.Met578Leu). This variant is present in population databases (rs766555892, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with ALAS2-related conditions. Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ALAS2 protein function with a negative predictive value of 95%. 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

0.13

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Pathogenic

0.26

CADD

Benign

DANN

Benign

0.78

DEOGEN2

Benign

0.20

.;T;T;.

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.89

D;.;D;D

M_CAP

Pathogenic

0.58

MetaRNN

Benign

0.23

T;T;T;T

MetaSVM

Uncertain

0.42

MutationAssessor

Benign

0.87

.;L;L;.

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-0.59

N;.;N;N

REVEL

Uncertain

0.48

Sift

Benign

0.24

T;.;T;T

Sift4G

Benign

0.45

T;.;T;T

Polyphen

0.0040

.;B;B;.

Vest4

0.36

MutPred

0.37

.;Gain of helix (P = 0.0078);Gain of helix (P = 0.0078);.;

MVP

0.99

MPC

0.46

ClinPred

0.077

GERP RS

5.4

Varity_R

0.61

gMVP

0.63

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