X-55009124-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000032.5(ALAS2):c.*56A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.011 in 1,172,771 control chromosomes in the GnomAD database, including 898 homozygotes. There are 3,456 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.057 (457 hom., 1739 hem., cov: 22)
  • Exomes 𝑓: 0.0062 (441 hom. 1717 hem.)
• Consequence: ALAS2 NM_000032.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.247

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant X-55009124-T-G is Benign according to our data. Variant chrX-55009124-T-G is described in ClinVar as [Benign]. Clinvar id is 368590.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.193 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALAS2	NM_000032.5	c.*56A>C		3_prime_UTR_variant	11/11	ENST00000650242.1
ALAS2	NM_001037967.4	c.*56A>C		3_prime_UTR_variant	10/10
ALAS2	NM_001037968.4	c.*56A>C		3_prime_UTR_variant	11/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALAS2	ENST00000650242.1	c.*56A>C		3_prime_UTR_variant	11/11		NM_000032.5	P1
ALAS2	ENST00000335854.8	c.*56A>C		3_prime_UTR_variant	10/10	2
ALAS2	ENST00000396198.7	c.*56A>C		3_prime_UTR_variant	11/11	5
ALAS2	ENST00000498636.1	c.*118A>C		3_prime_UTR_variant	5/5	3

Frequencies

GnomAD3 genomes AF: 0.0567 AC: 6313 AN: 111429 Hom.: 456 Cov.: 22 AF XY: 0.0514 AC XY: 1730 AN XY: 33683

Gnomad AFR AF: 0.197

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0182

Gnomad ASJ AF: 0.000753

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000378

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000678

Gnomad OTH AF: 0.0479

GnomAD4 exome AF: 0.00620 AC: 6582 AN: 1061287 Hom.: 441 Cov.: 27 AF XY: 0.00509 AC XY: 1717 AN XY: 337303

Gnomad4 AFR exome AF: 0.208

Gnomad4 AMR exome AF: 0.00958

Gnomad4 ASJ exome AF: 0.000694

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000668

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000241

Gnomad4 OTH exome AF: 0.0139

GnomAD4 genome AF: 0.0568 AC: 6329 AN: 111484 Hom.: 457 Cov.: 22 AF XY: 0.0515 AC XY: 1739 AN XY: 33748

Gnomad4 AFR AF: 0.197

Gnomad4 AMR AF: 0.0181

Gnomad4 ASJ AF: 0.000753

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000379

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000678

Gnomad4 OTH AF: 0.0473

Alfa AF: 0.0150 Hom.: 375

Bravo AF: 0.0650

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 28, 2018

- -

X-linked sideroblastic anemia 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	3.0
Dann	Benign	0.64
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs6612250; hg19: chrX-55035557;