dbSNP rs185631469: CSF2RA:c.1125+8G>A (chrX-1305535-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_172245.4(CSF2RA):c.1125+8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000273 in 1,614,018 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 231 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., 7 hem., cov: 32)

Exomes 𝑓: 0.00029 ( 0 hom. 224 hem. )

Consequence

CSF2RA
NM_172245.4 splice_region, intron

Scores

Splicing: ADA: 0.000008709

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.957

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-1.0).

BP6

Variant X-1305535-G-A is Benign according to our data. Variant chrX-1305535-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 537347.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000285 (417/1461672) while in subpopulation MID AF = 0.000521 (3/5762). AF 95% confidence interval is 0.00034. There are 0 homozygotes in GnomAdExome4. There are 224 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 7 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	Effect	Exon Rank	Protein	UniProt
CSF2RA	NM_172245.4	MANE Select	c.1125+8G>A	splice_region intron	N/A	NP_758448.1	P15509-1
CSF2RA	NM_001161530.2		c.1227+8G>A	splice_region intron	N/A	NP_001155002.1	P15509-7
CSF2RA	NM_001379153.1		c.1227+8G>A	splice_region intron	N/A	NP_001366082.1	P15509-7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CSF2RA	ENST00000381529.9	TSL:1 MANE Select	c.1125+8G>A	splice_region intron	N/A	ENSP00000370940.3	P15509-1
CSF2RA	ENST00000381509.8	TSL:1	c.1125+8G>A	splice_region intron	N/A	ENSP00000370920.3	P15509-2
CSF2RA	ENST00000381524.8	TSL:1	c.1125+8G>A	splice_region intron	N/A	ENSP00000370935.3	P15509-1

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000207

AC:

AN:

251162

AF XY:

0.000295

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000282

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.000285

AC:

417

AN:

1461672

Hom.:

Cov.:

AF XY:

0.000308

AC XY:

224

AN XY:

727146

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.0000447

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26132

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.000452

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000521

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000316

AC:

351

AN:

1111842

Other (OTH)

AF:

0.000331

AC:

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

107

134

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.000151

AC:

AN:

152346

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.0000962

AC:

AN:

41590

American (AMR)

AF:

0.0000654

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000250

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.521

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:

0.000204

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (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

0.070

(source)

DANN

Benign

0.28

PhyloP100

-0.96

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0000087

dbscSNV1_RF

Benign

0.0020

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