rs181719822

Positions:

• chrX-1294357-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_172245.4(CSF2RA):​c.676G>A​(p.Val226Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000415 in 1,613,760 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 338 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., 21 hem., cov: 32)
  • Exomes 𝑓: 0.00042 (0 hom. 317 hem.)
• Consequence: CSF2RA NM_172245.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.302

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]

CSF2RA (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.022605926).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000322 (49/152224) while in subpopulation AMR AF= 0.000589 (9/15276). AF 95% confidence interval is 0.000307. There are 0 homozygotes in gnomad4. There are 21 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Hemizygotes in GnomAd4 at 21 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CSF2RA	NM_172245.4	c.676G>A	p.Val226Ile	missense_variant	8/13	ENST00000381529.9	NP_758448.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CSF2RA	ENST00000381529.9	c.676G>A	p.Val226Ile	missense_variant	8/13	1	NM_172245.4	ENSP00000370940.3

Frequencies

GnomAD3 genomes AF: 0.000322 AC: 49 AN: 152106 Hom.: 0 Cov.: 32 AF XY: 0.000283 AC XY: 21 AN XY: 74300

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000590

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000549 AC: 138 AN: 251178 Hom.: 0 AF XY: 0.000575 AC XY: 78 AN XY: 135744

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000694

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000457

Gnomad FIN exome AF: 0.000647

Gnomad NFE exome AF: 0.000564

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000425 AC: 621 AN: 1461536 Hom.: 0 Cov.: 32 AF XY: 0.000436 AC XY: 317 AN XY: 727078

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000872

Gnomad4 ASJ exome AF: 0.00161

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000615

Gnomad4 FIN exome AF: 0.000543

Gnomad4 NFE exome AF: 0.000380

Gnomad4 OTH exome AF: 0.000431

GnomAD4 genome AF: 0.000322 AC: 49 AN: 152224 Hom.: 0 Cov.: 32 AF XY: 0.000282 AC XY: 21 AN XY: 74428

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000589

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.000474

Bravo AF: 0.000283

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000582 AC: 5

ExAC AF: 0.000544 AC: 66

EpiCase AF: 0.000327

EpiControl AF: 0.000415

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Surfactant metabolism dysfunction, pulmonary, 4 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 19, 2022	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 226 of the CSF2RA protein (p.Val226Ile). This variant is present in population databases (no rsID available, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with CSF2RA-related conditions. ClinVar contains an entry for this variant (Variation ID: 571570). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CSF2RA protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Apr 22, 2019	This CSF2RA variant (rs181719822) has been identified in large population datasets and the minor allele frequency is neither low enough to consider the variant rare (<0.1%) nor high enough to consider it a population polymorphism (>1%) within the Ashkenazi Jewish subpopulation (gnomAD: 17/10370 alleles; 0.16%, no homozygotes). This variant has not been reported in the literature to our knowledge and a single submitter in ClinVar classifies it as a variant of uncertain clinical significance. Two bioinformatic tools queried predict that this substitution would be tolerated. The valine residue at this position is absent from most species, however, it is highly evolutionarily conserved across the species where it is present. The clinical significance of c.676G>A is uncertain at this time. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	4.9
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T;.;.;T;T;T;.;.;.
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.58	.;T;T;.;T;T;T;T;T
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.023	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.20	D
MutationAssessor	Benign	1.2	L;.;L;L;.;L;L;L;L
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.78	N;N;N;N;N;N;N;N;N
REVEL	Benign	0.26
Sift	Benign	0.074	T;D;D;T;D;T;D;D;T
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D
Polyphen		0.95	P;.;.;P;.;P;P;P;P
Vest4		0.21
MVP		0.58
MPC		0.26
ClinPred		0.029	T
GERP RS		1.5
Varity_R		0.13

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: rs181719822; hg19: chrX-1413250; COSMIC: COSV62624356; COSMIC: COSV62624356;