rs892041887

Variant names:

• chrX-55009265-C-T
• rs892041887
• NM_000032.5:c.1679G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PP3_Strong

The NM_000032.5(ALAS2):​c.1679G>A​(p.Arg560His) variant causes a missense change. The variant allele was found at a frequency of 0.00000549 in 1,093,152 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R560C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000055 (0 hom. 0 hem.)
• Consequence: ALAS2 NM_000032.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 3.82
• Publications: 3 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_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 3 uncertain in NM_000032.5
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.945

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.1679G>A	p.Arg560His	missense	Exon 11 of 11	NP_000023.2	P22557-1
	ALAS2	NM_001037968.4		c.1640G>A	p.Arg547His	missense	Exon 11 of 11	NP_001033057.1	P22557-4
	ALAS2	NM_001037967.4		c.1568G>A	p.Arg523His	missense	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.1679G>A	p.Arg560His	missense	Exon 11 of 11	ENSP00000497236.1	P22557-1
	ALAS2	ENST00000396198.7	TSL:5	c.1640G>A	p.Arg547His	missense	Exon 11 of 11	ENSP00000379501.3	P22557-4
	ALAS2	ENST00000335854.8	TSL:2	c.1568G>A	p.Arg523His	missense	Exon 10 of 10	ENSP00000337131.4	P22557-2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD2 exomes AF: 0.00 AC: 0 AN: 167993 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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 AF: 0.00000549 AC: 6 AN: 1093152 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 359146

African (AFR) AF: 0.00 AC: 0 AN: 26356

American (AMR) AF: 0.00 AC: 0 AN: 34648

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19275

East Asian (EAS) AF: 0.00 AC: 0 AN: 30103

South Asian (SAS) AF: 0.0000378 AC: 2 AN: 52938

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40157

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4127

European-Non Finnish (NFE) AF: 0.00000476 AC: 4 AN: 839647

Other (OTH) AF: 0.00 AC: 0 AN: 45901

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.52	D
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		3.8
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-2.3	N
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.76
MutPred		0.81		Loss of solvent accessibility (P = 0.0674)
MVP		1.0
MPC		1.4
ClinPred		0.96	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.85
gMVP		0.78
Mutation Taster		=8/92	disease causing

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: rs892041887; hg19: chrX-55035698; COSMIC: COSV107369540; COSMIC: COSV107369540;