X-55009318-C-T

Position:

chrX-55009318-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000032.5(ALAS2):c.1626G>A(p.Ala542Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00276 in 1,201,370 control chromosomes in the GnomAD database, including 57 homozygotes. There are 879 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.015 ( 39 hom., 435 hem., cov: 22)

Exomes 𝑓: 0.0015 ( 18 hom. 444 hem. )

Consequence

ALAS2
NM_000032.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.633

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant X-55009318-C-T is Benign according to our data. Variant chrX-55009318-C-T is described in ClinVar as [Benign]. Clinvar id is 368591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.633 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0504 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALAS2	NM_000032.5 linkuse as main transcript	c.1626G>A	p.Ala542Ala	synonymous_variant	11/11	ENST00000650242.1	NP_000023.2	P22557-1
ALAS2	NM_001037968.4 linkuse as main transcript	c.1587G>A	p.Ala529Ala	synonymous_variant	11/11		NP_001033057.1	P22557-4
ALAS2	NM_001037967.4 linkuse as main transcript	c.1515G>A	p.Ala505Ala	synonymous_variant	10/10		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.1626G>A	p.Ala542Ala	synonymous_variant	11/11		NM_000032.5	ENSP00000497236.1	P22557-1
ALAS2	ENST00000498636.1 linkuse as main transcript	c.752G>A	p.Arg251Gln	missense_variant	5/5	3		ENSP00000495662.1	A0A2R8Y6N3
ALAS2	ENST00000396198.7 linkuse as main transcript	c.1587G>A	p.Ala529Ala	synonymous_variant	11/11	5		ENSP00000379501.3	P22557-4
ALAS2	ENST00000335854.8 linkuse as main transcript	c.1515G>A	p.Ala505Ala	synonymous_variant	10/10	2		ENSP00000337131.4	P22557-2

Frequencies

GnomAD3 genomes

AF:

0.0150

AC:

1662

AN:

111054

Hom.:

Cov.:

AF XY:

0.0131

AC XY:

434

AN XY:

33256

show subpopulations

Gnomad AFR

AF:

0.0525

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00400

Gnomad ASJ

AF:

0.000379

Gnomad EAS

AF:

0.000282

Gnomad SAS

AF:

0.000771

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000943

Gnomad OTH

AF:

0.00939

GnomAD3 exomes

AF:

0.00429

AC:

690

AN:

161019

Hom.:

AF XY:

0.00286

AC XY:

148

AN XY:

51745

show subpopulations

Gnomad AFR exome

AF:

0.0532

Gnomad AMR exome

AF:

0.00182

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000781

Gnomad SAS exome

AF:

0.000780

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000101

Gnomad OTH exome

AF:

0.00270

GnomAD4 exome

AF:

0.00151

AC:

1648

AN:

1090263

Hom.:

Cov.:

AF XY:

0.00124

AC XY:

444

AN XY:

357193

show subpopulations

Gnomad4 AFR exome

AF:

0.0514

Gnomad4 AMR exome

AF:

0.00248

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000343

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000203

Gnomad4 OTH exome

AF:

0.00356

GnomAD4 genome

AF:

0.0150

AC:

1665

AN:

111107

Hom.:

Cov.:

AF XY:

0.0131

AC XY:

435

AN XY:

33319

show subpopulations

Gnomad4 AFR

AF:

0.0525

Gnomad4 AMR

AF:

0.00400

Gnomad4 ASJ

AF:

0.000379

Gnomad4 EAS

AF:

0.000283

Gnomad4 SAS

AF:

0.000773

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000943

Gnomad4 OTH

AF:

0.00927

Alfa

AF:

0.00841

Hom.:

Bravo

AF:

0.0173

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

ALAS2-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 01, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

X-linked sideroblastic anemia 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

2.7

DANN

Benign

0.75

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.7

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