chrX-55009318-C-T

Position:

• chrX-55009318-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000032.5(ALAS2):​c.1626G>A​(p.Ala542=) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.633

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]

ACMG classification

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	UniProt
ALAS2	NM_000032.5	c.1626G>A	p.Ala542=	synonymous_variant	11/11	ENST00000650242.1
ALAS2	NM_001037968.4	c.1587G>A	p.Ala529=	synonymous_variant	11/11
ALAS2	NM_001037967.4	c.1515G>A	p.Ala505=	synonymous_variant	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALAS2	ENST00000650242.1	c.1626G>A	p.Ala542=	synonymous_variant	11/11		NM_000032.5	P1
ALAS2	ENST00000498636.1	c.755G>A	p.Arg252Gln	missense_variant	5/5	3
ALAS2	ENST00000396198.7	c.1587G>A	p.Ala529=	synonymous_variant	11/11	5
ALAS2	ENST00000335854.8	c.1515G>A	p.Ala505=	synonymous_variant	10/10	2

Frequencies

GnomAD3 genomes AF: 0.0150 AC: 1662 AN: 111054 Hom.: 39 Cov.: 22 AF XY: 0.0131 AC XY: 434 AN XY: 33256

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.: 10 AF XY: 0.00286 AC XY: 148 AN XY: 51745

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.: 18 Cov.: 31 AF XY: 0.00124 AC XY: 444 AN XY: 357193

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.: 39 Cov.: 22 AF XY: 0.0131 AC XY: 435 AN XY: 33319

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.: 68

Bravo AF: 0.0173

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -

ALAS2-related disorder Benign:1

Benign, criteria provided, single submitter

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

Other links and lift over

dbSNP: rs6612251; hg19: chrX-55035751;