dbSNP rs140581875: CSF2RA:p.Thr93Thr (chrX-1288578-A-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_172245.4(CSF2RA):c.279A>G(p.Thr93Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00124 in 1,613,958 control chromosomes in the GnomAD database, including 6 homozygotes. There are 1,060 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0015 ( 0 hom., 123 hem., cov: 32)

Exomes 𝑓: 0.0012 ( 6 hom. 937 hem. )

Consequence

CSF2RA
NM_172245.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -2.35

Publications

0 publications found

Variant links:

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: DEFINITIVE, STRONG Submitted by: ClinGen, 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-1.04).

BP6

Variant X-1288578-A-G is Benign according to our data. Variant chrX-1288578-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 227279.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.35 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00154 (235/152294) while in subpopulation AMR AF = 0.00255 (39/15280). AF 95% confidence interval is 0.00192. There are 0 homozygotes in GnomAd4. There are 123 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 123 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CSF2RA	NM_172245.4	MANE Select	c.279A>G	p.Thr93Thr	synonymous	Exon 5 of 13	NP_758448.1	P15509-1
CSF2RA	NM_001161530.2		c.279A>G	p.Thr93Thr	synonymous	Exon 5 of 14	NP_001155002.1	P15509-7
CSF2RA	NM_001379153.1		c.279A>G	p.Thr93Thr	synonymous	Exon 4 of 13	NP_001366082.1	P15509-7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CSF2RA	ENST00000381529.9	TSL:1 MANE Select	c.279A>G	p.Thr93Thr	synonymous	Exon 5 of 13	ENSP00000370940.3	P15509-1
CSF2RA	ENST00000381509.8	TSL:1	c.279A>G	p.Thr93Thr	synonymous	Exon 5 of 13	ENSP00000370920.3	P15509-2
CSF2RA	ENST00000381524.8	TSL:1	c.279A>G	p.Thr93Thr	synonymous	Exon 5 of 13	ENSP00000370935.3	P15509-1

Frequencies

GnomAD3 genomes

AF:

0.00154

AC:

234

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000893

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00256

Gnomad ASJ

AF:

0.0118

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00148

Gnomad OTH

AF:

0.00382

GnomAD2 exomes

AF:

0.00162

AC:

406

AN:

251182

AF XY:

0.00176

show subpopulations

Gnomad AFR exome

AF:

0.00172

Gnomad AMR exome

AF:

0.00116

Gnomad ASJ exome

AF:

0.0122

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.00154

Gnomad OTH exome

AF:

0.00245

GnomAD4 exome

AF:

0.00120

AC:

1761

AN:

1461664

Hom.:

Cov.:

AF XY:

0.00129

AC XY:

937

AN XY:

727140

show subpopulations

African (AFR)

AF:

0.00164

AC:

AN:

33472

American (AMR)

AF:

0.00136

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0101

AC:

264

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000696

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.000187

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00989

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00100

AC:

1117

AN:

1111834

Other (OTH)

AF:

0.00227

AC:

137

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

113

227

340

454

567

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

168

210

<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:

0.00154

AC:

235

AN:

152294

Hom.:

Cov.:

AF XY:

0.00165

AC XY:

123

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.000914

AC:

AN:

41566

American (AMR)

AF:

0.00255

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.0118

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00148

AC:

101

AN:

68022

Other (OTH)

AF:

0.00378

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Bravo

AF:

0.00172

EpiCase

AF:

0.00207

EpiControl

AF:

0.00308

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (1)

Surfactant metabolism dysfunction, pulmonary, 4 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.0

CADD

Benign

0.021

(source)

DANN

Benign

0.14

PhyloP100

-2.4

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

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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

Computational scores

Splicing

Publications

Other links and lift over