Genetic Variant NM_000032.5:c.1676G>C (chrX-55009268-C-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2PP5_ModerateBP4

The NM_000032.5(ALAS2):c.1676G>C(p.Arg559Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R559H) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 23)

Consequence

ALAS2
NM_000032.5 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: -0.306

Publications

5 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 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant X-55009268-C-G is Pathogenic according to our data. Variant chrX-55009268-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 214100.Status of the report is criteria_provided_single_submitter, 1 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.3853199). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000032.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ALAS2	NM_000032.5	MANE Select	c.1676G>C	p.Arg559Pro	missense	Exon 11 of 11	NP_000023.2	P22557-1
ALAS2	NM_001037968.4		c.1637G>C	p.Arg546Pro	missense	Exon 11 of 11	NP_001033057.1	P22557-4
ALAS2	NM_001037967.4		c.1565G>C	p.Arg522Pro	missense	Exon 10 of 10	NP_001033056.1	P22557-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ALAS2	ENST00000650242.1	MANE Select	c.1676G>C	p.Arg559Pro	missense	Exon 11 of 11	ENSP00000497236.1	P22557-1
ALAS2	ENST00000396198.7	TSL:5	c.1637G>C	p.Arg546Pro	missense	Exon 11 of 11	ENSP00000379501.3	P22557-4
ALAS2	ENST00000335854.8	TSL:2	c.1565G>C	p.Arg522Pro	missense	Exon 10 of 10	ENSP00000337131.4	P22557-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Likely pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Uncertain

0.063

BayesDel_noAF

Benign

-0.15

CADD

Benign

7.9

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.39

FATHMM_MKL

Benign

0.25

LIST_S2

Uncertain

0.95

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.39

MetaSVM

Uncertain

0.44

MutationAssessor

Uncertain

2.0

PhyloP100

-0.31

PrimateAI

Benign

0.22

PROVEAN

Uncertain

-2.4

REVEL

Uncertain

0.43

Sift

Uncertain

0.018

Sift4G

Uncertain

0.023

Polyphen

0.74

Vest4

0.40

MutPred

0.63

Loss of helix (P = 0.079)

MVP

0.78

MPC

1.1

ClinPred

0.87

GERP RS

-3.5

Varity_R

0.89

gMVP

0.90

Mutation Taster

=87/13

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over