X-55009056-G-A

Position:

• chrX-55009056-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000032.5(ALAS2):​c.*124C>T variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00395 in 905,640 control chromosomes in the GnomAD database, including 34 homozygotes. There are 1,051 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0037 (3 hom., 188 hem., cov: 23)
  • Exomes 𝑓: 0.0040 (31 hom. 863 hem.)
• Consequence: ALAS2 NM_000032.5 splice_region
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.83

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]

APEX2 (HGNC:17889): (apurinic/apyrimidinic endodeoxyribonuclease 2) Apurinic/apyrimidinic (AP) sites occur frequently in DNA molecules by spontaneous hydrolysis, by DNA damaging agents or by DNA glycosylases that remove specific abnormal bases. AP sites are pre-mutagenic lesions that can prevent normal DNA replication so the cell contains systems to identify and repair such sites. Class II AP endonucleases cleave the phosphodiester backbone 5' to the AP site. This gene encodes a protein shown to have a weak class II AP endonuclease activity. Most of the encoded protein is located in the nucleus but some is also present in mitochondria. This protein may play an important role in both nuclear and mitochondrial base excision repair. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Nov 2012]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant X-55009056-G-A is Benign according to our data. Variant chrX-55009056-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 913522.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00368 (414/112422) while in subpopulation NFE AF= 0.00248 (132/53323). AF 95% confidence interval is 0.00213. There are 3 homozygotes in gnomad4. There are 188 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALAS2	NM_000032.5	c.*124C>T		splice_region_variant	11/11	ENST00000650242.1	NP_000023.2
APEX2	NM_014481.4	c.*1621G>A		splice_region_variant	6/6	ENST00000374987.4	NP_055296.2
ALAS2	NM_000032.5	c.*124C>T		3_prime_UTR_variant	11/11	ENST00000650242.1	NP_000023.2
APEX2	NM_014481.4	c.*1621G>A		3_prime_UTR_variant	6/6	ENST00000374987.4	NP_055296.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALAS2	ENST00000650242.1	c.*124C>T		splice_region_variant	11/11		NM_000032.5	ENSP00000497236.1
APEX2	ENST00000374987.4	c.*1621G>A		splice_region_variant	6/6	1	NM_014481.4	ENSP00000364126.3
ALAS2	ENST00000650242	c.*124C>T		3_prime_UTR_variant	11/11		NM_000032.5	ENSP00000497236.1
APEX2	ENST00000374987.4	c.*1621G>A		3_prime_UTR_variant	6/6	1	NM_014481.4	ENSP00000364126.3

Frequencies

GnomAD3 genomes AF: 0.00368 AC: 414 AN: 112368 Hom.: 3 Cov.: 23 AF XY: 0.00545 AC XY: 188 AN XY: 34520

Gnomad AFR AF: 0.000324

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00122

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0418

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00248

Gnomad OTH AF: 0.00265

GnomAD4 exome AF: 0.00398 AC: 3160 AN: 793218 Hom.: 31 Cov.: 12 AF XY: 0.00410 AC XY: 863 AN XY: 210654

Gnomad4 AFR exome AF: 0.000310

Gnomad4 AMR exome AF: 0.000986

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000201

Gnomad4 FIN exome AF: 0.0414

Gnomad4 NFE exome AF: 0.00251

Gnomad4 OTH exome AF: 0.00354

GnomAD4 genome AF: 0.00368 AC: 414 AN: 112422 Hom.: 3 Cov.: 23 AF XY: 0.00544 AC XY: 188 AN XY: 34584

Gnomad4 AFR AF: 0.000323

Gnomad4 AMR AF: 0.00122

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0418

Gnomad4 NFE AF: 0.00248

Gnomad4 OTH AF: 0.00262

Alfa AF: 0.00324 Hom.: 19

Bravo AF: 0.00150

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 31, 2018

- -

X-linked sideroblastic anemia 1 Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	8.1
DANN	Benign	0.47

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: rs145843014; hg19: chrX-55035489;