5-132075761-C-T

Position:

• chr5-132075761-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000758.4(CSF2):​c.344C>T​(p.Thr115Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00149 in 1,608,986 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (6 hom.)
• Consequence: CSF2 NM_000758.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0440

Genes affected

CSF2 (HGNC:2434): (colony stimulating factor 2) The protein encoded by this gene is a cytokine that controls the production, differentiation, and function of granulocytes and macrophages. The active form of the protein is found extracellularly as a homodimer. This gene has been localized to a cluster of related genes at chromosome region 5q31, which is known to be associated with interstitial deletions in the 5q- syndrome and acute myelogenous leukemia. Other genes in the cluster include those encoding interleukins 4, 5, and 13. This gene plays a role in promoting tissue inflammation. Elevated levels of cytokines, including the one produced by this gene, have been detected in SARS-CoV-2 infected patients that develop acute respiratory distress syndrome. Mice deficient in this gene or its receptor develop pulmonary alveolar proteinosis. [provided by RefSeq, Aug 2020]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007443011).
• BP6: Variant 5-132075761-C-T is Benign according to our data. Variant chr5-132075761-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 710325.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 209 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CSF2	NM_000758.4	c.344C>T	p.Thr115Ile	missense_variant	4/4	ENST00000296871.4	NP_000749.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CSF2	ENST00000296871.4	c.344C>T	p.Thr115Ile	missense_variant	4/4	1	NM_000758.4	ENSP00000296871.2

Frequencies

GnomAD3 genomes AF: 0.00137 AC: 209 AN: 152176 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00187

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00128 AC: 317 AN: 246826 Hom.: 1 AF XY: 0.00117 AC XY: 157 AN XY: 133808

Gnomad AFR exome AF: 0.000311

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.00567

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000330

Gnomad NFE exome AF: 0.00170

Gnomad OTH exome AF: 0.00197

GnomAD4 exome AF: 0.00150 AC: 2183 AN: 1456692 Hom.: 6 Cov.: 30 AF XY: 0.00145 AC XY: 1049 AN XY: 724968

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.00125

Gnomad4 ASJ exome AF: 0.00651

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.000225

Gnomad4 NFE exome AF: 0.00162

Gnomad4 OTH exome AF: 0.00214

GnomAD4 genome AF: 0.00137 AC: 209 AN: 152294 Hom.: 0 Cov.: 33 AF XY: 0.00132 AC XY: 98 AN XY: 74458

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.00314

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00187

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00194 Hom.: 2

Bravo AF: 0.00174

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00291 AC: 25

ExAC AF: 0.00113 AC: 137

EpiCase AF: 0.00218

EpiControl AF: 0.00202

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 26, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.53	D
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.0080	T
MetaRNN	Benign	0.0074	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-4.1	D
REVEL	Benign	0.025
Sift	Benign	0.057	T
Sift4G	Benign	0.073	T
Polyphen		0.13	B
Vest4		0.085
MVP		0.25
MPC		0.47
ClinPred		0.017	T
GERP RS		2.6
Varity_R		0.31
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2069640; hg19: chr5-131411454; COSMIC: COSV99735627; COSMIC: COSV99735627;