X-55009297-A-G

Position:

chrX-55009297-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000032.5(ALAS2):c.1647T>C(p.Asp549=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000173 in 1,202,928 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 66 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00091 ( 0 hom., 25 hem., cov: 22)

Exomes 𝑓: 0.000098 ( 0 hom. 41 hem. )

Consequence

ALAS2
NM_000032.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.0100

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=-0.89).

BP6

Variant X-55009297-A-G is Benign according to our data. Variant chrX-55009297-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 388258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.01 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000909 (101/111072) while in subpopulation AFR AF= 0.00311 (95/30533). AF 95% confidence interval is 0.00261. There are 0 homozygotes in gnomad4. There are 25 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 25 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ALAS2	NM_000032.5 linkuse as main transcript	c.1647T>C	p.Asp549=	synonymous_variant	11/11	ENST00000650242.1	NP_000023.2
ALAS2	NM_001037968.4 linkuse as main transcript	c.1608T>C	p.Asp536=	synonymous_variant	11/11		NP_001033057.1
ALAS2	NM_001037967.4 linkuse as main transcript	c.1536T>C	p.Asp512=	synonymous_variant	10/10		NP_001033056.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALAS2	ENST00000650242.1 linkuse as main transcript	c.1647T>C	p.Asp549=	synonymous_variant	11/11		NM_000032.5	ENSP00000497236	P1	P22557-1
ALAS2	ENST00000498636.1 linkuse as main transcript	c.776T>C	p.Met259Thr	missense_variant	5/5	3		ENSP00000495662
ALAS2	ENST00000396198.7 linkuse as main transcript	c.1608T>C	p.Asp536=	synonymous_variant	11/11	5		ENSP00000379501		P22557-4
ALAS2	ENST00000335854.8 linkuse as main transcript	c.1536T>C	p.Asp512=	synonymous_variant	10/10	2		ENSP00000337131		P22557-2

Frequencies

GnomAD3 genomes

AF:

0.000910

AC:

101

AN:

111018

Hom.:

Cov.:

AF XY:

0.000753

AC XY:

AN XY:

33210

show subpopulations

Gnomad AFR

AF:

0.00312

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000477

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00417

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000219

AC:

AN:

164582

Hom.:

AF XY:

0.000186

AC XY:

AN XY:

53656

show subpopulations

Gnomad AFR exome

AF:

0.00257

Gnomad AMR exome

AF:

0.000230

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000980

AC:

107

AN:

1091856

Hom.:

Cov.:

AF XY:

0.000114

AC XY:

AN XY:

358170

show subpopulations

Gnomad4 AFR exome

AF:

0.00326

Gnomad4 AMR exome

AF:

0.000290

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000238

Gnomad4 OTH exome

AF:

0.000196

GnomAD4 genome

AF:

0.000909

AC:

101

AN:

111072

Hom.:

Cov.:

AF XY:

0.000751

AC XY:

AN XY:

33274

show subpopulations

Gnomad4 AFR

AF:

0.00311

Gnomad4 AMR

AF:

0.000477

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000498

Hom.:

Bravo

AF:

0.000929

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 17, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 30, 2016	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. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

6.2

DANN

Benign

0.59

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

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