X-55013526-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_000032.5(ALAS2):c.1560C>A(p.Pro520Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00386 in 1,209,514 control chromosomes in the GnomAD database, including 13 homozygotes. There are 1,518 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0037 ( 1 hom., 129 hem., cov: 22)

Exomes 𝑓: 0.0039 ( 12 hom. 1389 hem. )

Consequence

ALAS2
NM_000032.5 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 0.216

Publications

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

ALAS2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.52).

BP6

Variant X-55013526-G-T is Benign according to our data. Variant chrX-55013526-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 214089.

BP7

Synonymous conserved (PhyloP=0.216 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00366 (409/111598) while in subpopulation AMR AF = 0.00694 (73/10513). AF 95% confidence interval is 0.00566. There are 1 homozygotes in GnomAd4. There are 129 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 129 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALAS2	NM_000032.5 link	c.1560C>A	p.Pro520Pro	synonymous_variant	Exon 10 of 11	ENST00000650242.1	NP_000023.2	P22557-1
ALAS2	NM_001037968.4 link	c.1521C>A	p.Pro507Pro	synonymous_variant	Exon 10 of 11		NP_001033057.1	P22557-4
ALAS2	NM_001037967.4 link	c.1449C>A	p.Pro483Pro	synonymous_variant	Exon 9 of 10		NP_001033056.1	P22557-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ALAS2	ENST00000650242.1 link	c.1560C>A	p.Pro520Pro	synonymous_variant	Exon 10 of 11		NM_000032.5	ENSP00000497236.1	P22557-1
ALAS2	ENST00000396198.7 link	c.1521C>A	p.Pro507Pro	synonymous_variant	Exon 10 of 11	5		ENSP00000379501.3	P22557-4
ALAS2	ENST00000335854.8 link	c.1449C>A	p.Pro483Pro	synonymous_variant	Exon 9 of 10	2		ENSP00000337131.4	P22557-2
ALAS2	ENST00000498636.1 link	c.726+1221C>A		intron_variant	Intron 4 of 4	3		ENSP00000495662.1	A0A2R8Y6N3

Frequencies

GnomAD3 genomes

AF:

0.00367

AC:

409

AN:

111544

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000326

Gnomad AMI

AF:

0.0160

Gnomad AMR

AF:

0.00695

Gnomad ASJ

AF:

0.00680

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00416

Gnomad MID

AF:

0.00420

Gnomad NFE

AF:

0.00495

Gnomad OTH

AF:

0.00535

GnomAD2 exomes

AF:

0.00365

AC:

666

AN:

182616

AF XY:

0.00359

show subpopulations

Gnomad AFR exome

AF:

0.000304

Gnomad AMR exome

AF:

0.00234

Gnomad ASJ exome

AF:

0.00725

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00545

Gnomad NFE exome

AF:

0.00516

Gnomad OTH exome

AF:

0.00576

GnomAD4 exome

AF:

0.00388

AC:

4261

AN:

1097916

Hom.:

Cov.:

AF XY:

0.00382

AC XY:

1389

AN XY:

363284

show subpopulations

African (AFR)

AF:

0.000455

AC:

AN:

26400

American (AMR)

AF:

0.00264

AC:

AN:

35201

Ashkenazi Jewish (ASJ)

AF:

0.00650

AC:

126

AN:

19372

East Asian (EAS)

AF:

0.00

AC:

AN:

30199

South Asian (SAS)

AF:

0.000813

AC:

AN:

54109

European-Finnish (FIN)

AF:

0.00639

AC:

259

AN:

40511

Middle Eastern (MID)

AF:

0.00822

AC:

AN:

4136

European-Non Finnish (NFE)

AF:

0.00414

AC:

3484

AN:

841902

Other (OTH)

AF:

0.00453

AC:

209

AN:

46086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

168

337

505

674

842

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

224

336

448

560

<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:

0.00366

AC:

409

AN:

111598

Hom.:

Cov.:

AF XY:

0.00382

AC XY:

129

AN XY:

33766

show subpopulations

African (AFR)

AF:

0.000325

AC:

AN:

30726

American (AMR)

AF:

0.00694

AC:

AN:

10513

Ashkenazi Jewish (ASJ)

AF:

0.00680

AC:

AN:

2648

East Asian (EAS)

AF:

0.00

AC:

AN:

3539

South Asian (SAS)

AF:

0.00

AC:

AN:

2615

European-Finnish (FIN)

AF:

0.00416

AC:

AN:

6008

Middle Eastern (MID)

AF:

0.00459

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.00495

AC:

263

AN:

53131

Other (OTH)

AF:

0.00528

AC:

AN:

1514

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00502

Hom.:

Bravo

AF:

0.00428

EpiCase

AF:

0.00704

EpiControl

AF:

0.00630

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

May 01, 2016

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Jun 09, 2014

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Nov 25, 2018

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

X-linked sideroblastic anemia 1

Benign:2

May 18, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.52

CADD

Benign

5.3

(source)

DANN

Benign

0.75

PhyloP100

0.22

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=98/2

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over