NM_000760.4:c.1037A>G

Variant names:

• chr1-36472100-T-C
• rs3917974
• NM_000760.4:c.1037A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000760.4(CSF3R):​c.1037A>G​(p.Gln346Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00533 in 1,613,786 control chromosomes in the GnomAD database, including 238 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q346P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.024 (114 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (124 hom.)
• Consequence: CSF3R NM_000760.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.111
• Publications: 14 publications found

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: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ENSG00000297367 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00173527).
• BP6: Variant 1-36472100-T-C is Benign according to our data. Variant chr1-36472100-T-C is described in ClinVar as Benign. ClinVar VariationId is 256787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0771 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSF3R	NM_000760.4	MANE Select	c.1037A>G	p.Gln346Arg	missense	Exon 9 of 17	NP_000751.1	Q99062-1
	CSF3R	NM_156039.3		c.1037A>G	p.Gln346Arg	missense	Exon 9 of 17	NP_724781.1	Q99062-3
	CSF3R	NM_172313.3		c.1037A>G	p.Gln346Arg	missense	Exon 9 of 18	NP_758519.1	Q99062-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSF3R	ENST00000373106.6	TSL:1 MANE Select	c.1037A>G	p.Gln346Arg	missense	Exon 9 of 17	ENSP00000362198.2	Q99062-1
	CSF3R	ENST00000373103.5	TSL:1	c.1037A>G	p.Gln346Arg	missense	Exon 9 of 17	ENSP00000362195.1	Q99062-3
	CSF3R	ENST00000373104.5	TSL:1	c.1037A>G	p.Gln346Arg	missense	Exon 9 of 18	ENSP00000362196.1	Q99062-4

Frequencies

GnomAD3 genomes AF: 0.0240 AC: 3653 AN: 152136 Hom.: 113 Cov.: 32

Gnomad AFR AF: 0.0793

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0131

Gnomad ASJ AF: 0.00980

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00137

Gnomad OTH AF: 0.0192

GnomAD2 exomes AF: 0.00699 AC: 1754 AN: 250824 AF XY: 0.00548

Gnomad AFR exome AF: 0.0789

Gnomad AMR exome AF: 0.00515

Gnomad ASJ exome AF: 0.0111

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00127

Gnomad OTH exome AF: 0.00620

GnomAD4 exome AF: 0.00338 AC: 4939 AN: 1461532 Hom.: 124 Cov.: 32 AF XY: 0.00312 AC XY: 2270 AN XY: 727074

African (AFR) AF: 0.0837 AC: 2803 AN: 33478

American (AMR) AF: 0.00552 AC: 247 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0123 AC: 321 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000232 AC: 20 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53068

Middle Eastern (MID) AF: 0.00936 AC: 54 AN: 5768

European-Non Finnish (NFE) AF: 0.000969 AC: 1077 AN: 1112008

Other (OTH) AF: 0.00690 AC: 417 AN: 60394

GnomAD4 genome AF: 0.0241 AC: 3665 AN: 152254 Hom.: 114 Cov.: 32 AF XY: 0.0234 AC XY: 1741 AN XY: 74448

African (AFR) AF: 0.0793 AC: 3295 AN: 41538

American (AMR) AF: 0.0131 AC: 200 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00980 AC: 34 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00137 AC: 93 AN: 68012

Other (OTH) AF: 0.0190 AC: 40 AN: 2108

Alfa AF: 0.00949 Hom.: 90

Bravo AF: 0.0278

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0744 AC: 328

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.00810 AC: 984

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.00180

EpiControl AF: 0.00207

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Autosomal recessive severe congenital neutropenia due to CSF3R deficiency (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	8.9
DANN	Benign	0.68
DEOGEN2	Benign	0.095	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		-0.11
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.93	N
REVEL	Benign	0.034
Sift	Benign	0.30	T
Sift4G	Benign	0.29	T
Polyphen		0.29	B
Vest4		0.049
MVP		0.42
MPC		0.33
ClinPred		0.015	T
GERP RS		1.6
Varity_R		0.080
gMVP		0.37
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3917974; hg19: chr1-36937701;