Genetic Variant NM_000760.4:c.1919C>A (chr1-36467597-G-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP5

The NM_000760.4(CSF3R):c.1919C>A(p.Thr640Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T640I) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Consequence

CSF3R
NM_000760.4 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 0.234

Publications

27 publications found

Variant links:

Genes affected

CSF3R (HGNC:2439): (colony stimulating factor 3 receptor) The protein encoded by this gene is the receptor for colony stimulating factor 3, a cytokine that controls the production, differentiation, and function of granulocytes. The encoded protein, which is a member of the family of cytokine receptors, may also function in some cell surface adhesion or recognition processes. Alternatively spliced transcript variants have been described. Mutations in this gene are a cause of Kostmann syndrome, also known as severe congenital neutropenia. [provided by RefSeq, Aug 2010]

CSF3R Gene-Disease associations (from GenCC):

hereditary neutrophilia
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
autosomal recessive severe congenital neutropenia due to CSF3R deficiency
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

CSF3R links:

ENSG00000297367 (HGNC:):

ENSG00000297367 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-36467597-G-T is Pathogenic according to our data. Variant chr1-36467597-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 16005.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000760.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CSF3R	NM_000760.4	MANE Select	c.1919C>A	p.Thr640Asn	missense	Exon 15 of 17	NP_000751.1
CSF3R	NM_156039.3		c.1919C>A	p.Thr640Asn	missense	Exon 15 of 17	NP_724781.1
CSF3R	NM_172313.3		c.1919C>A	p.Thr640Asn	missense	Exon 15 of 18	NP_758519.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CSF3R	ENST00000373106.6	TSL:1 MANE Select	c.1919C>A	p.Thr640Asn	missense	Exon 15 of 17	ENSP00000362198.2
CSF3R	ENST00000373103.5	TSL:1	c.1919C>A	p.Thr640Asn	missense	Exon 15 of 17	ENSP00000362195.1
CSF3R	ENST00000373104.5	TSL:1	c.1919C>A	p.Thr640Asn	missense	Exon 15 of 18	ENSP00000362196.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Hereditary neutrophilia

Pathogenic:1

Aug 03, 2009

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.53

CADD

Benign

8.6

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.21

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.53

M_CAP

Benign

0.031

MetaRNN

Uncertain

0.74

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

PhyloP100

0.23

PrimateAI

Benign

0.23

PROVEAN

Benign

-2.0

REVEL

Benign

0.11

Sift

Benign

0.071

Sift4G

Benign

0.078

Polyphen

0.0030

Vest4

0.74

MutPred

0.88

Gain of sheet (P = 0.0344)

MVP

0.50

MPC

0.35

ClinPred

0.070

GERP RS

-0.53

Varity_R

0.088

gMVP

0.75

Mutation Taster

=3/97

disease causing (ClinVar)

(source)

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over