NM_000032.5:c.*124C>T

Variant names:

• chrX-55009056-G-A
• rs145843014
• NM_000032.5:c.*124C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 0 publications found

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

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000032.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALAS2	NM_000032.5	MANE Select	c.*124C>T		splice_region	Exon 11 of 11	NP_000023.2	P22557-1
	APEX2	NM_014481.4	MANE Select	c.*1621G>A		splice_region	Exon 6 of 6	NP_055296.2
	ALAS2	NM_000032.5	MANE Select	c.*124C>T		3_prime_UTR	Exon 11 of 11	NP_000023.2	P22557-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALAS2	ENST00000650242.1	MANE Select	c.*124C>T		splice_region	Exon 11 of 11	ENSP00000497236.1	P22557-1
	APEX2	ENST00000374987.4	TSL:1 MANE Select	c.*1621G>A		splice_region	Exon 6 of 6	ENSP00000364126.3	Q9UBZ4
	ALAS2	ENST00000650242.1	MANE Select	c.*124C>T		3_prime_UTR	Exon 11 of 11	ENSP00000497236.1	P22557-1

Frequencies

GnomAD3 genomes AF: 0.00368 AC: 414 AN: 112368 Hom.: 3 Cov.: 23

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

African (AFR) AF: 0.000310 AC: 6 AN: 19350

American (AMR) AF: 0.000986 AC: 24 AN: 24348

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14968

East Asian (EAS) AF: 0.00 AC: 0 AN: 25743

South Asian (SAS) AF: 0.000201 AC: 8 AN: 39740

European-Finnish (FIN) AF: 0.0414 AC: 1503 AN: 36273

Middle Eastern (MID) AF: 0.000821 AC: 2 AN: 2437

European-Non Finnish (NFE) AF: 0.00251 AC: 1492 AN: 595027

Other (OTH) AF: 0.00354 AC: 125 AN: 35332

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

African (AFR) AF: 0.000323 AC: 10 AN: 30947

American (AMR) AF: 0.00122 AC: 13 AN: 10674

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2658

East Asian (EAS) AF: 0.00 AC: 0 AN: 3589

South Asian (SAS) AF: 0.00 AC: 0 AN: 2702

European-Finnish (FIN) AF: 0.0418 AC: 255 AN: 6099

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.00248 AC: 132 AN: 53323

Other (OTH) AF: 0.00262 AC: 4 AN: 1529

Alfa AF: 0.00324 Hom.: 19

Bravo AF: 0.00150

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	X-linked sideroblastic anemia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	8.1
DANN	Benign	0.47
PhyloP100		1.8
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs145843014; hg19: chrX-55035489;