rs138964358

Positions:

• chrX-1290354-G-A
• chrX-1290354-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_172245.4(CSF2RA):​c.491G>A​(p.Arg164Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00776 in 1,613,084 control chromosomes in the GnomAD database, including 71 homozygotes. There are 6,063 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R164W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0053 (2 hom., 365 hem., cov: 31)
  • Exomes 𝑓: 0.0080 (69 hom. 5698 hem.)
• Consequence: CSF2RA NM_172245.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.243

Genes affected

CSF2RA (HGNC:2435): (colony stimulating factor 2 receptor subunit alpha) The protein encoded by this gene is the alpha subunit of the heterodimeric receptor for colony stimulating factor 2, a cytokine which controls the production, differentiation, and function of granulocytes and macrophages. The encoded protein is a member of the cytokine family of receptors. This gene is found in the pseudoautosomal region (PAR) of the X and Y chromosomes. Multiple transcript variants encoding different isoforms have been found for this gene, with some of the isoforms being membrane-bound and others being soluble. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014863938).
• BP6: Variant X-1290354-G-A is Benign according to our data. Variant chrX-1290354-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 163003.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 = 0.00532 (809/151998) while in subpopulation NFE AF= 0.00868 (590/67982). AF 95% confidence interval is 0.0081. There are 2 homozygotes in gnomad4. There are 365 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CSF2RA	NM_172245.4	c.491G>A	p.Arg164Gln	missense_variant	7/13	ENST00000381529.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CSF2RA	ENST00000381529.9	c.491G>A	p.Arg164Gln	missense_variant	7/13	1	NM_172245.4	A2

Frequencies

GnomAD3 genomes AF: 0.00534 AC: 811 AN: 151886 Hom.: 2 Cov.: 31 AF XY: 0.00492 AC XY: 365 AN XY: 74172

Gnomad AFR AF: 0.00179

Gnomad AMI AF: 0.0362

Gnomad AMR AF: 0.00348

Gnomad ASJ AF: 0.00692

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00190

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00868

Gnomad OTH AF: 0.00480

GnomAD3 exomes AF: 0.00512 AC: 1285 AN: 251150 Hom.: 8 AF XY: 0.00497 AC XY: 675 AN XY: 135728

Gnomad AFR exome AF: 0.00185

Gnomad AMR exome AF: 0.00335

Gnomad ASJ exome AF: 0.00953

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00124

Gnomad FIN exome AF: 0.00249

Gnomad NFE exome AF: 0.00799

Gnomad OTH exome AF: 0.00718

GnomAD4 exome AF: 0.00801 AC: 11705 AN: 1461086 Hom.: 69 Cov.: 32 AF XY: 0.00784 AC XY: 5698 AN XY: 726852

Gnomad4 AFR exome AF: 0.00161

Gnomad4 AMR exome AF: 0.00378

Gnomad4 ASJ exome AF: 0.00877

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.00151

Gnomad4 FIN exome AF: 0.00279

Gnomad4 NFE exome AF: 0.00949

Gnomad4 OTH exome AF: 0.00689

GnomAD4 genome AF: 0.00532 AC: 809 AN: 151998 Hom.: 2 Cov.: 31 AF XY: 0.00491 AC XY: 365 AN XY: 74294

Gnomad4 AFR AF: 0.00178

Gnomad4 AMR AF: 0.00341

Gnomad4 ASJ AF: 0.00692

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00190

Gnomad4 NFE AF: 0.00868

Gnomad4 OTH AF: 0.00475

Bravo AF: 0.00541

TwinsUK AF: 0.00890 AC: 33

ALSPAC AF: 0.0106 AC: 41

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00768 AC: 66

ExAC AF: 0.00471 AC: 572

EpiCase AF: 0.00780

EpiControl AF: 0.00723

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 21, 2013

Arg164Gln in exon 8 of CSF2RA: This variant is not expected to have clinical sig nificance because it has been identified in 0.8% (66/8592) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs138964358). -

Surfactant metabolism dysfunction, pulmonary, 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	0.19
DANN	Benign	0.88
DEOGEN2	Benign	0.26	T;.;.;T;T;T;.;.;.;.
FATHMM_MKL	Benign	0.00041	N
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.015	T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Benign	-0.28	N;.;N;N;.;N;N;N;N;N
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	0.39	N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.13
Sift	Benign	0.14	T;T;T;T;T;T;T;T;T;T
Sift4G	Uncertain	0.042	D;D;D;D;T;D;T;T;T;D
Polyphen		0.93	P;.;.;P;.;P;D;P;P;P
Vest4		0.12
MVP		0.49
MPC		0.14
ClinPred		0.012	T
GERP RS		-0.36
Varity_R		0.10

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs138964358; hg19: chrX-1409247;