dbSNP rs137852301: ALAS2:p.Phe165Leu (chrX-55021195-G-T) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1PM2PP3_StrongPP5_Moderate

The NM_000032.5(ALAS2):c.495C>A(p.Phe165Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 23)

Consequence

ALAS2
NM_000032.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 4.27

Publications

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

ALAS2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000032.5

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.972

PP5

Variant X-55021195-G-T is Pathogenic according to our data. Variant chrX-55021195-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 10470.Status of the report is criteria_provided_single_submitter, 1 stars.

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.495C>A	p.Phe165Leu	missense	Exon 5 of 11	NP_000023.2	P22557-1
ALAS2	NM_001037968.4		c.456C>A	p.Phe152Leu	missense	Exon 5 of 11	NP_001033057.1	P22557-4
ALAS2	NM_001037967.4		c.384C>A	p.Phe128Leu	missense	Exon 4 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.495C>A	p.Phe165Leu	missense	Exon 5 of 11	ENSP00000497236.1	P22557-1
ALAS2	ENST00000396198.7	TSL:5	c.456C>A	p.Phe152Leu	missense	Exon 5 of 11	ENSP00000379501.3	P22557-4
ALAS2	ENST00000335854.8	TSL:2	c.384C>A	p.Phe128Leu	missense	Exon 4 of 10	ENSP00000337131.4	P22557-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

X-linked sideroblastic anemia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.60

BayesDel_noAF

Pathogenic

0.63

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.75

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.31

MetaRNN

Pathogenic

0.97

MetaSVM

Uncertain

-0.18

MutationAssessor

Pathogenic

3.1

PhyloP100

4.3

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-5.9

REVEL

Pathogenic

0.94

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

0.99

Vest4

0.71

MutPred

0.87

Loss of methylation at K166 (P = 0.0384)

MVP

1.0

MPC

1.5

ClinPred

1.0

GERP RS

3.1

Varity_R

0.97

gMVP

0.99

Mutation Taster

=11/89

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