X-55009249-C-T

Variant names:

• chrX-55009249-C-T
• rs149747514
• NM_000032.5:c.1695G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_000032.5(ALAS2):​c.1695G>A​(p.Glu565Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
  • Failed GnomAD Quality Control
• Consequence: ALAS2 NM_000032.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.779
• Publications: 2 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP7: Synonymous conserved (PhyloP=0.779 with no splicing effect.

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.1695G>A	p.Glu565Glu	synonymous	Exon 11 of 11	NP_000023.2	P22557-1
	ALAS2	NM_001037968.4		c.1656G>A	p.Glu552Glu	synonymous	Exon 11 of 11	NP_001033057.1	P22557-4
	ALAS2	NM_001037967.4		c.1584G>A	p.Glu528Glu	synonymous	Exon 10 of 10	NP_001033056.1	P22557-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALAS2	ENST00000650242.1	MANE Select	c.1695G>A	p.Glu565Glu	synonymous	Exon 11 of 11	ENSP00000497236.1	P22557-1
	ALAS2	ENST00000498636.1	TSL:3	c.821G>A	p.Ser274Asn	missense	Exon 5 of 5	ENSP00000495662.1	A0A2R8Y6N3
	ALAS2	ENST00000396198.7	TSL:5	c.1656G>A	p.Glu552Glu	synonymous	Exon 11 of 11	ENSP00000379501.3	P22557-4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.00000585 AC: 1 AN: 170826 AF XY: 0.0000175

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000378

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.14e-7 AC: 1 AN: 1094277 Hom.: 0 Cov.: 31 AF XY: 0.00000278 AC XY: 1 AN XY: 360057

African (AFR) AF: 0.00 AC: 0 AN: 26371

American (AMR) AF: 0.0000287 AC: 1 AN: 34808

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19305

East Asian (EAS) AF: 0.00 AC: 0 AN: 30135

South Asian (SAS) AF: 0.00 AC: 0 AN: 53134

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40223

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4131

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 840228

Other (OTH) AF: 0.00 AC: 0 AN: 45942

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	9.7
DANN	Benign	0.81
PhyloP100		0.78

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: rs149747514; hg19: chrX-55035682;