chrX-1294373-C-T

Variant names:

• chrX-1294373-C-T
• rs149974131
• NM_172245.4:c.692C>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_172245.4(CSF2RA):​c.692C>T​(p.Thr231Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000519 in 1,613,734 control chromosomes in the GnomAD database, including 1 homozygotes. There are 412 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. T231T) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., 22 hem., cov: 32)
  • Exomes 𝑓: 0.00055 (1 hom. 390 hem.)
• Consequence: CSF2RA NM_172245.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.47
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• surfactant metabolism dysfunction, pulmonary, 4

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• hereditary pulmonary alveolar proteinosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15778312).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00025 (38/152182) while in subpopulation NFE AF = 0.000426 (29/68036). AF 95% confidence interval is 0.000304. There are 0 homozygotes in GnomAd4. There are 22 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Hemizygotes in GnomAd4 at 22 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_172245.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSF2RA	NM_172245.4	MANE Select	c.692C>T	p.Thr231Met	missense	Exon 8 of 13	NP_758448.1
	CSF2RA	NM_001161530.2		c.692C>T	p.Thr231Met	missense	Exon 8 of 14	NP_001155002.1
	CSF2RA	NM_001379153.1		c.692C>T	p.Thr231Met	missense	Exon 7 of 13	NP_001366082.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSF2RA	ENST00000381529.9	TSL:1 MANE Select	c.692C>T	p.Thr231Met	missense	Exon 8 of 13	ENSP00000370940.3
	CSF2RA	ENST00000381509.8	TSL:1	c.692C>T	p.Thr231Met	missense	Exon 8 of 13	ENSP00000370920.3
	CSF2RA	ENST00000381524.8	TSL:1	c.692C>T	p.Thr231Met	missense	Exon 8 of 13	ENSP00000370935.3

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000259 AC: 65 AN: 251176 AF XY: 0.000295

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000217

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000449

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000547 AC: 800 AN: 1461552 Hom.: 1 Cov.: 32 AF XY: 0.000536 AC XY: 390 AN XY: 727090

African (AFR) AF: 0.0000896 AC: 3 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.000227 AC: 9 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.000150 AC: 8 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.000670 AC: 745 AN: 1111768

Other (OTH) AF: 0.000580 AC: 35 AN: 60372

GnomAD4 genome AF: 0.000250 AC: 38 AN: 152182 Hom.: 0 Cov.: 32 AF XY: 0.000296 AC XY: 22 AN XY: 74350

African (AFR) AF: 0.000169 AC: 7 AN: 41446

American (AMR) AF: 0.0000655 AC: 1 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000426 AC: 29 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Bravo AF: 0.000329

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000582 AC: 5

ExAC AF: 0.000231 AC: 28

EpiCase AF: 0.000327

EpiControl AF: 0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Surfactant metabolism dysfunction, pulmonary, 4 Uncertain:1

Aug 23, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 231 of the CSF2RA protein (p.Thr231Met). This variant is present in population databases (no rsID available, gnomAD 0.05%). 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: 578948). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). 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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	17
DANN	Benign	0.91
DEOGEN2	Benign	0.30	T
FATHMM_MKL	Benign	0.043	N
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.16	T
MetaSVM	Uncertain	0.070	D
MutationAssessor	Benign	1.1	L
PhyloP100		1.5
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.14
Sift	Uncertain	0.027	D
Sift4G	Uncertain	0.044	D
Polyphen		0.38	B
Vest4		0.33
MVP		0.64
MPC		0.17
ClinPred		0.034	T
GERP RS		1.5
Varity_R		0.076
Mutation Taster		=95/5	polymorphism

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: rs149974131; hg19: chrX-1413266; COSMIC: COSV62623706; COSMIC: COSV62623706;