1-36471458-A-G

Variant names:

• chr1-36471458-A-G
• rs3917981
• NM_000760.4:c.1260T>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000760.4(CSF3R):​c.1260T>C​(p.Thr420Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.559 in 1,613,338 control chromosomes in the GnomAD database, including 255,538 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.60 (27479 hom., cov: 33)
  • Exomes 𝑓: 0.56 (228059 hom.)
• Consequence: CSF3R NM_000760.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.764
• Publications: 25 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

ENSG00000297367 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.018).
• BP6: Variant 1-36471458-A-G is Benign according to our data. Variant chr1-36471458-A-G is described in ClinVar as Benign. ClinVar VariationId is 256790.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.764 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.715 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSF3R	NM_000760.4	MANE Select	c.1260T>C	p.Thr420Thr	synonymous	Exon 10 of 17	NP_000751.1
	CSF3R	NM_156039.3		c.1260T>C	p.Thr420Thr	synonymous	Exon 10 of 17	NP_724781.1
	CSF3R	NM_172313.3		c.1260T>C	p.Thr420Thr	synonymous	Exon 10 of 18	NP_758519.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSF3R	ENST00000373106.6	TSL:1 MANE Select	c.1260T>C	p.Thr420Thr	synonymous	Exon 10 of 17	ENSP00000362198.2
	CSF3R	ENST00000373103.5	TSL:1	c.1260T>C	p.Thr420Thr	synonymous	Exon 10 of 17	ENSP00000362195.1
	CSF3R	ENST00000373104.5	TSL:1	c.1260T>C	p.Thr420Thr	synonymous	Exon 10 of 18	ENSP00000362196.1

Frequencies

GnomAD3 genomes AF: 0.595 AC: 90384 AN: 151902 Hom.: 27455 Cov.: 33

Gnomad AFR AF: 0.722

Gnomad AMI AF: 0.612

Gnomad AMR AF: 0.482

Gnomad ASJ AF: 0.547

Gnomad EAS AF: 0.427

Gnomad SAS AF: 0.681

Gnomad FIN AF: 0.615

Gnomad MID AF: 0.589

Gnomad NFE AF: 0.549

Gnomad OTH AF: 0.592

GnomAD2 exomes AF: 0.554 AC: 139121 AN: 251314 AF XY: 0.565

Gnomad AFR exome AF: 0.726

Gnomad AMR exome AF: 0.397

Gnomad ASJ exome AF: 0.545

Gnomad EAS exome AF: 0.408

Gnomad FIN exome AF: 0.606

Gnomad NFE exome AF: 0.555

Gnomad OTH exome AF: 0.566

GnomAD4 exome AF: 0.555 AC: 811310 AN: 1461316 Hom.: 228059 Cov.: 50 AF XY: 0.560 AC XY: 406743 AN XY: 726972

African (AFR) AF: 0.728 AC: 24369 AN: 33474

American (AMR) AF: 0.403 AC: 18043 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.550 AC: 14367 AN: 26132

East Asian (EAS) AF: 0.428 AC: 16998 AN: 39700

South Asian (SAS) AF: 0.685 AC: 59038 AN: 86244

European-Finnish (FIN) AF: 0.602 AC: 32172 AN: 53404

Middle Eastern (MID) AF: 0.570 AC: 3280 AN: 5752

European-Non Finnish (NFE) AF: 0.548 AC: 609035 AN: 1111526

Other (OTH) AF: 0.563 AC: 34008 AN: 60362

GnomAD4 genome AF: 0.595 AC: 90456 AN: 152022 Hom.: 27479 Cov.: 33 AF XY: 0.598 AC XY: 44414 AN XY: 74314

African (AFR) AF: 0.722 AC: 29943 AN: 41486

American (AMR) AF: 0.482 AC: 7363 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.547 AC: 1898 AN: 3470

East Asian (EAS) AF: 0.428 AC: 2206 AN: 5160

South Asian (SAS) AF: 0.681 AC: 3283 AN: 4822

European-Finnish (FIN) AF: 0.615 AC: 6500 AN: 10564

Middle Eastern (MID) AF: 0.585 AC: 172 AN: 294

European-Non Finnish (NFE) AF: 0.549 AC: 37290 AN: 67916

Other (OTH) AF: 0.589 AC: 1245 AN: 2112

Alfa AF: 0.568 Hom.: 69205

Bravo AF: 0.583

Asia WGS AF: 0.579 AC: 2011 AN: 3478

EpiCase AF: 0.562

EpiControl AF: 0.563

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Autosomal recessive severe congenital neutropenia due to CSF3R deficiency Benign:2

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nov 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.37
DANN	Benign	0.32
PhyloP100		-0.76
PromoterAI		0.012	Neutral
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: rs3917981; hg19: chr1-36937059; COSMIC: COSV58963206; COSMIC: COSV58963206;