Genetic Variant CSF1:p.Ala3Pro (chr1-109911030-G-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_000757.6(CSF1):c.7G>C(p.Ala3Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000998 in 1,001,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A3T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000010 ( 0 hom. )

Consequence

CSF1
NM_000757.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0600

Publications

0 publications found

Variant links:

Genes affected

CSF1 (HGNC:2432): (colony stimulating factor 1) The protein encoded by this gene is a cytokine that controls the production, differentiation, and function of macrophages. The active form of the protein is found extracellularly as a disulfide-linked homodimer, and is thought to be produced by proteolytic cleavage of membrane-bound precursors. The encoded protein may be involved in development of the placenta. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Sep 2011]

CSF1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3949169).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSF1	NM_000757.6 link	c.7G>C	p.Ala3Pro	missense_variant	Exon 1 of 9	ENST00000329608.11	NP_000748.4	P09603-1A0A024R0A1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSF1	ENST00000329608.11 link	c.7G>C	p.Ala3Pro	missense_variant	Exon 1 of 9	1	NM_000757.6	ENSP00000327513.6		P09603-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.98e-7

AC:

AN:

1001760

Hom.:

Cov.:

AF XY:

0.00000210

AC XY:

AN XY:

476190

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

19730

American (AMR)

AF:

0.00

AC:

AN:

7714

Ashkenazi Jewish (ASJ)

AF:

0.0000919

AC:

AN:

10878

East Asian (EAS)

AF:

0.00

AC:

AN:

17170

South Asian (SAS)

AF:

0.00

AC:

AN:

21792

European-Finnish (FIN)

AF:

0.00

AC:

AN:

15016

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2476

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

869758

Other (OTH)

AF:

0.00

AC:

AN:

37226

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

.;T;T;T;.;.

Eigen

Benign

0.10

Eigen_PC

Benign

0.049

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.65

T;.;T;T;T;T

M_CAP

Pathogenic

0.32

MetaRNN

Benign

0.39

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

.;L;.;L;L;L

PhyloP100

0.060

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-1.5

N;N;N;N;N;N

REVEL

Benign

0.15

Sift

Pathogenic

0.0

D;D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;D

Polyphen

1.0, 0.18

.;D;.;D;B;D

Vest4

0.30, 0.29, 0.23, 0.22

MutPred

0.69

Gain of glycosylation at A3 (P = 0.0331);Gain of glycosylation at A3 (P = 0.0331);Gain of glycosylation at A3 (P = 0.0331);Gain of glycosylation at A3 (P = 0.0331);Gain of glycosylation at A3 (P = 0.0331);Gain of glycosylation at A3 (P = 0.0331);

MVP

0.29

MPC

0.61

ClinPred

0.88

GERP RS

2.0

PromoterAI

-0.061

Neutral

(source)

Varity_R

0.33

gMVP

0.34

Mutation Taster

=80/20

polymorphism

(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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1-109911030-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over