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 -16 ACMG points: 4P and 20B. PM1 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. 15/21 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

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 -16 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_000032.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-55009268-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id 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 [Likely_benign]. Clinvar id is 214090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-55009268-C-T is described in Lovd as [Likely_benign].
• 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 FAILED quality control check.
• BS2: High Hemizygotes in GnomAd4 at 51 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALAS2	NM_000032.5	c.1676G>A	p.Arg559His	missense_variant	Exon 11 of 11	ENST00000650242.1	NP_000023.2
APEX2	NM_014481.4	c.*1833C>T		downstream_gene_variant		ENST00000374987.4	NP_055296.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALAS2	ENST00000650242.1	c.1676G>A	p.Arg559His	missense_variant	Exon 11 of 11		NM_000032.5	ENSP00000497236.1
APEX2	ENST00000374987.4	c.*1833C>T		downstream_gene_variant		1	NM_014481.4	ENSP00000364126.3

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

Gnomad4 AFR exome AF: 0.000341 AC: 9 AN: 26358

Gnomad4 AMR exome AF: 0.00323 AC: 112 AN: 34631

Gnomad4 ASJ exome AF: 0.0102 AC: 197 AN: 19271

Gnomad4 EAS exome AF: 0.0000332 AC: 1 AN: 30097

Gnomad4 SAS exome AF: 0.000132 AC: 7 AN: 52943

Gnomad4 FIN exome AF: 0.000150 AC: 6 AN: 40129

Gnomad4 NFE exome AF: 0.00281 AC: 2363 AN: 839535

Gnomad4 Remaining exome 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

Gnomad4 AFR AF: 0.000230 AC: 0.000229885 AN: 0.000229885

Gnomad4 AMR AF: 0.00163 AC: 0.00162773 AN: 0.00162773

Gnomad4 ASJ AF: 0.00945 AC: 0.0094518 AN: 0.0094518

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.00242 AC: 0.00241925 AN: 0.00241925

Gnomad4 OTH AF: 0.000669 AC: 0.000668896 AN: 0.000668896

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

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 04, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 26562225, 21653323, 22995991, 15678587, 22740690, 30678654, 22269113, 20848343, 15678585, 16121195) -

Oct 30, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

May 22, 2017

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ALAS2-related disorder Benign:1

Oct 12, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

X-linked sideroblastic anemia 1 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

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;T;.
FATHMM_MKL	Benign	0.056	N
LIST_S2	Uncertain	0.86	D;.;D;D
MetaRNN	Benign	0.0092	T;T;T;T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	1.3	.;L;L;.
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.55	N;.;N;N
REVEL	Benign	0.27
Sift	Benign	0.59	T;.;T;T
Sift4G	Benign	0.34	T;.;T;T
Polyphen		0.0030	.;B;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

Publications

LitVar

Other links and lift over

dbSNP: rs145704441; hg19: chrX-55035701; COSMIC: COSV99043817; COSMIC: COSV99043817;