X-55013526-G-T

Position:

chrX-55013526-G-T

Variant summary

Our verdict is Benign. Variant got -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

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 214089.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=5}.

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 male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 129 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALAS2	NM_000032.5 linkuse as main transcript	c.1560C>A	p.Pro520Pro	synonymous_variant	10/11	ENST00000650242.1	NP_000023.2	P22557-1
ALAS2	NM_001037968.4 linkuse as main transcript	c.1521C>A	p.Pro507Pro	synonymous_variant	10/11		NP_001033057.1	P22557-4
ALAS2	NM_001037967.4 linkuse as main transcript	c.1449C>A	p.Pro483Pro	synonymous_variant	9/10		NP_001033056.1	P22557-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ALAS2	ENST00000650242.1 linkuse as main transcript	c.1560C>A	p.Pro520Pro	synonymous_variant	10/11		NM_000032.5	ENSP00000497236.1	P22557-1
ALAS2	ENST00000396198.7 linkuse as main transcript	c.1521C>A	p.Pro507Pro	synonymous_variant	10/11	5		ENSP00000379501.3	P22557-4
ALAS2	ENST00000335854.8 linkuse as main transcript	c.1449C>A	p.Pro483Pro	synonymous_variant	9/10	2		ENSP00000337131.4	P22557-2
ALAS2	ENST00000498636.1 linkuse as main transcript	c.726+1221C>A		intron_variant		3		ENSP00000495662.1	A0A2R8Y6N3

Frequencies

GnomAD3 genomes

AF:

0.00367

AC:

409

AN:

111544

Hom.:

Cov.:

AF XY:

0.00383

AC XY:

129

AN XY:

33702

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

GnomAD3 exomes

AF:

0.00365

AC:

666

AN:

182616

Hom.:

AF XY:

0.00359

AC XY:

241

AN XY:

67168

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 SAS exome

AF:

0.000631

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

Gnomad4 AFR exome

AF:

0.000455

Gnomad4 AMR exome

AF:

0.00264

Gnomad4 ASJ exome

AF:

0.00650

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000813

Gnomad4 FIN exome

AF:

0.00639

Gnomad4 NFE exome

AF:

0.00414

Gnomad4 OTH exome

AF:

0.00453

GnomAD4 genome

AF:

0.00366

AC:

409

AN:

111598

Hom.:

Cov.:

AF XY:

0.00382

AC XY:

129

AN XY:

33766

show subpopulations

Gnomad4 AFR

AF:

0.000325

Gnomad4 AMR

AF:

0.00694

Gnomad4 ASJ

AF:

0.00680

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00416

Gnomad4 NFE

AF:

0.00495

Gnomad4 OTH

AF:

0.00528

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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2016	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2014	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. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 25, 2018	- -

X-linked sideroblastic anemia 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.52

CADD

Benign

5.3

DANN

Benign

0.75

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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