X-55009268-C-T

Variant names:

• chrX-55009268-C-T
• rs145704441
• NM_000032.5:c.1676G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM5 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000032.5(ALAS2):​c.1676G>A​(p.Arg559His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00248 in 1,203,790 control chromosomes in the GnomAD database, including 5 homozygotes. There are 932 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R559P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., 51 hem., cov: 23)
  • Exomes 𝑓: 0.0026 (4 hom. 881 hem.)
• Consequence: ALAS2 NM_000032.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.306
• Publications: 5 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 -18 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-55009268-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 214100.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0092430115).
• BP6: Variant X-55009268-C-T is Benign according to our data. Variant chrX-55009268-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 214090.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 = 0.00161 (178/110810) while in subpopulation NFE AF = 0.00242 (128/52909). AF 95% confidence interval is 0.00208. There are 1 homozygotes in GnomAd4. There are 51 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 51 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.1676G>A	p.Arg559His	missense	Exon 11 of 11	NP_000023.2	P22557-1
	ALAS2	NM_001037968.4		c.1637G>A	p.Arg546His	missense	Exon 11 of 11	NP_001033057.1	P22557-4
	ALAS2	NM_001037967.4		c.1565G>A	p.Arg522His	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.1676G>A	p.Arg559His	missense	Exon 11 of 11	ENSP00000497236.1	P22557-1
	ALAS2	ENST00000396198.7	TSL:5	c.1637G>A	p.Arg546His	missense	Exon 11 of 11	ENSP00000379501.3	P22557-4
	ALAS2	ENST00000335854.8	TSL:2	c.1565G>A	p.Arg522His	missense	Exon 10 of 10	ENSP00000337131.4	P22557-2

Frequencies

GnomAD3 genomes AF: 0.00161 AC: 178 AN: 110760 Hom.: 1 Cov.: 23

Gnomad AFR AF: 0.000230

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00163

Gnomad ASJ AF: 0.00945

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00242

Gnomad OTH AF: 0.000678

GnomAD2 exomes AF: 0.00227 AC: 381 AN: 167537 AF XY: 0.00190

Gnomad AFR exome AF: 0.000498

Gnomad AMR exome AF: 0.00335

Gnomad ASJ exome AF: 0.0114

Gnomad EAS exome AF: 0.0000760

Gnomad FIN exome AF: 0.0000695

Gnomad NFE exome AF: 0.00240

Gnomad OTH exome AF: 0.00615

GnomAD4 exome AF: 0.00257 AC: 2813 AN: 1092980 Hom.: 4 Cov.: 31 AF XY: 0.00245 AC XY: 881 AN XY: 359068

African (AFR) AF: 0.000341 AC: 9 AN: 26358

American (AMR) AF: 0.00323 AC: 112 AN: 34631

Ashkenazi Jewish (ASJ) AF: 0.0102 AC: 197 AN: 19271

East Asian (EAS) AF: 0.0000332 AC: 1 AN: 30097

South Asian (SAS) AF: 0.000132 AC: 7 AN: 52943

European-Finnish (FIN) AF: 0.000150 AC: 6 AN: 40129

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

European-Non Finnish (NFE) AF: 0.00281 AC: 2363 AN: 839535

Other (OTH) AF: 0.00257 AC: 118 AN: 45889

GnomAD4 genome AF: 0.00161 AC: 178 AN: 110810 Hom.: 1 Cov.: 23 AF XY: 0.00154 AC XY: 51 AN XY: 33022

African (AFR) AF: 0.000230 AC: 7 AN: 30450

American (AMR) AF: 0.00163 AC: 17 AN: 10444

Ashkenazi Jewish (ASJ) AF: 0.00945 AC: 25 AN: 2645

East Asian (EAS) AF: 0.00 AC: 0 AN: 3520

South Asian (SAS) AF: 0.00 AC: 0 AN: 2549

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5897

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.00242 AC: 128 AN: 52909

Other (OTH) AF: 0.000669 AC: 1 AN: 1495

Alfa AF: 0.00234 Hom.: 104

Bravo AF: 0.00162

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00173 AC: 5

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.00312 AC: 21

ExAC AF: 0.00222 AC: 269

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	ALAS2-related disorder (1)
-	-	1	not specified (1)
-	-	1	X-linked sideroblastic anemia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	0.37
DANN	Benign	0.89
DEOGEN2	Benign	0.20	T
FATHMM_MKL	Benign	0.056	N
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0092	T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	1.3	L
PhyloP100		-0.31
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.55	N
REVEL	Benign	0.27
Sift	Benign	0.59	T
Sift4G	Benign	0.34	T
Polyphen		0.0030	B
Vest4		0.13
MVP		0.75
MPC		0.62
ClinPred		0.0060	T
GERP RS		-3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.17
gMVP		0.52
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: rs145704441; hg19: chrX-55035701; COSMIC: COSV99043817; COSMIC: COSV99043817;