Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 8P and 16B. PVS1BP6_Very_StrongBS1BS2

The ENST00000381529.9(CSF2RA):c.728_729insGTCGGTGAGACAGAAAG(p.Tyr243ValfsTer16) variant causes a frameshift, stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00221 in 1,613,822 control chromosomes in the GnomAD database, including 70 homozygotes. There are 1,603 hemizygotes in GnomAD. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.012 ( 33 hom., 831 hem., cov: 32)

Exomes 𝑓: 0.0012 ( 37 hom. 772 hem. )

Consequence

CSF2RA
ENST00000381529.9 frameshift, stop_gained

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.0960

Publications

0 publications found

Variant links:

COSMIC-nc: COSV107442181

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

CSF2RA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

BP6

Variant X-1294453-C-CACAGAAAGGTCGGTGAG is Benign according to our data. Variant chrX-1294453-C-CACAGAAAGGTCGGTGAG is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 469626.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0115 (1753/152266) while in subpopulation AFR AF = 0.0395 (1643/41548). AF 95% confidence interval is 0.038. There are 33 homozygotes in GnomAd4. There are 831 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 33 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000381529.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
CSF2RA	NM_172245.4	MANE Select	c.774_780+10dupCAGAAAGGTCGGTGAGA	intron	N/A	NP_758448.1
CSF2RA	NM_001161530.2		c.774_780+10dupCAGAAAGGTCGGTGAGA	intron	N/A	NP_001155002.1
CSF2RA	NM_001379153.1		c.774_780+10dupCAGAAAGGTCGGTGAGA	intron	N/A	NP_001366082.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CSF2RA	ENST00000381529.9	TSL:1 MANE Select	c.728_729insGTCGGTGAGACAGAAAG	p.Tyr243ValfsTer16	frameshift stop_gained	Exon 8 of 13	ENSP00000370940.3
CSF2RA	ENST00000381509.8	TSL:1	c.728_729insGTCGGTGAGACAGAAAG	p.Tyr243ValfsTer16	frameshift stop_gained	Exon 8 of 13	ENSP00000370920.3
CSF2RA	ENST00000381524.8	TSL:1	c.728_729insGTCGGTGAGACAGAAAG	p.Tyr243ValfsTer16	frameshift stop_gained	Exon 8 of 13	ENSP00000370935.3

Frequencies

GnomAD3 genomes

AF:

0.0114

AC:

1735

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0392

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00498

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.0115

GnomAD2 exomes

AF:

0.00313

AC:

785

AN:

251082

AF XY:

0.00217

show subpopulations

Gnomad AFR exome

AF:

0.0413

Gnomad AMR exome

AF:

0.00257

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000141

Gnomad OTH exome

AF:

0.000816

GnomAD4 exome

AF:

0.00124

AC:

1814

AN:

1461556

Hom.:

Cov.:

AF XY:

0.00106

AC XY:

772

AN XY:

727098

show subpopulations

African (AFR)

AF:

0.0424

AC:

1418

AN:

33462

American (AMR)

AF:

0.00277

AC:

124

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000812

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53354

Middle Eastern (MID)

AF:

0.00418

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.0000639

AC:

AN:

1111834

Other (OTH)

AF:

0.00280

AC:

169

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

197

295

394

492

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

138

184

230

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0115

AC:

1753

AN:

152266

Hom.:

Cov.:

AF XY:

0.0112

AC XY:

831

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.0395

AC:

1643

AN:

41548

American (AMR)

AF:

0.00497

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68020

Other (OTH)

AF:

0.0114

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

162

244

325

406

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

Surfactant metabolism dysfunction, pulmonary, 4 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.096

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs377345813

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over