6-167003778-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_007045.4(CEP43):c.267T>G(p.Phe89Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000246 in 1,611,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: CEP43 NM_007045.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.347

Genes affected

CEP43 (HGNC:17012): (centrosomal protein 43) This gene encodes a largely hydrophilic centrosomal protein that is required for anchoring microtubules to subcellular structures. A t(6;8)(q27;p11) chromosomal translocation, fusing this gene and the fibroblast growth factor receptor 1 (FGFR1) gene, has been found in cases of myeloproliferative disorder. The resulting chimeric protein contains the N-terminal leucine-rich region of this encoded protein fused to the catalytic domain of FGFR1. Alterations in this gene may also be associated with Crohn's disease, Graves' disease, and vitiligo. Alternatively spliced transcript variants that encode different proteins have been identified. [provided by RefSeq, Jul 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09546235).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CEP43	NM_007045.4	c.267T>G	p.Phe89Leu	missense_variant	4/13	ENST00000366847.9
CEP43	NM_194429.3	c.267T>G	p.Phe89Leu	missense_variant	4/12
CEP43	NM_001278690.2	c.267T>G	p.Phe89Leu	missense_variant	4/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEP43	ENST00000366847.9	c.267T>G	p.Phe89Leu	missense_variant	4/13	1	NM_007045.4	P4

Frequencies

GnomAD3 genomes AF: 0.000361 AC: 55 AN: 152234 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000632

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000315 AC: 79 AN: 250608 Hom.: 0 AF XY: 0.000332 AC XY: 45 AN XY: 135546

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00219

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.000510

Gnomad NFE exome AF: 0.000309

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000234 AC: 341 AN: 1459488 Hom.: 0 Cov.: 28 AF XY: 0.000223 AC XY: 162 AN XY: 726180

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00238

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.000414

Gnomad4 NFE exome AF: 0.000193

Gnomad4 OTH exome AF: 0.000448

GnomAD4 genome AF: 0.000361 AC: 55 AN: 152352 Hom.: 0 Cov.: 33 AF XY: 0.000349 AC XY: 26 AN XY: 74498

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000632

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000505 Hom.: 0

Bravo AF: 0.000246

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000305 AC: 37

Asia WGS AF: 0.000289 AC: 1 AN: 3470

EpiCase AF: 0.000274

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 06, 2022

The c.267T>G (p.F89L) alteration is located in exon 4 (coding exon 4) of the FGFR1OP gene. This alteration results from a T to G substitution at nucleotide position 267, causing the phenylalanine (F) at amino acid position 89 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.16
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.40	T;.;.
Eigen	Benign	0.086
Eigen_PC	Benign	-0.072
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.095	T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.1	M;.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-5.0	D;.;D
REVEL	Uncertain	0.40
Sift	Uncertain	0.010	D;.;D
Sift4G	Uncertain	0.020	D;T;D
Polyphen		1.0	D;.;D
Vest4		0.55
MutPred		0.88		Loss of helix (P = 0.1706);Loss of helix (P = 0.1706);Loss of helix (P = 0.1706);
MVP		0.55
MPC		0.086
ClinPred		0.42	T
GERP RS		-6.1
Varity_R		0.79
gMVP		0.61

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

LitVar

Other links and lift over

dbSNP: rs140062109; hg19: chr6-167417266;