6-167004399-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_007045.4(CEP43):c.436G>A(p.Glu146Lys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000419 in 1,432,134 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000042 ( 0 hom. )

Consequence

CEP43
NM_007045.4 missense, splice_region

Scores

Splicing: ADA: 0.0001710

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.76

Variant links:

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]

CEP43 links:

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ACMG classification

Classification made for transcript

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=0.1921699).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CEP43	NM_007045.4 linkuse as main transcript	c.436G>A	p.Glu146Lys	missense_variant, splice_region_variant	5/13	ENST00000366847.9
CEP43	NM_194429.3 linkuse as main transcript	c.436G>A	p.Glu146Lys	missense_variant, splice_region_variant	5/12
CEP43	NM_001278690.2 linkuse as main transcript	c.436G>A	p.Glu146Lys	missense_variant, splice_region_variant	5/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEP43	ENST00000366847.9 linkuse as main transcript	c.436G>A	p.Glu146Lys	missense_variant, splice_region_variant	5/13	1	NM_007045.4	P4	O95684-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000870

AC:

AN:

229946

Hom.:

AF XY:

0.00000803

AC XY:

AN XY:

124474

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000186

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000419

AC:

AN:

1432134

Hom.:

Cov.:

AF XY:

0.00000421

AC XY:

AN XY:

712206

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000125

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000364

Gnomad4 OTH exome

AF:

0.0000170

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000378

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 27, 2022

The c.436G>A (p.E146K) alteration is located in exon 5 (coding exon 5) of the FGFR1OP gene. This alteration results from a G to A substitution at nucleotide position 436, causing the glutamic acid (E) at amino acid position 146 to be replaced by a lysine (K). 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

Benign

0.095

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.39

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Benign

0.074

T;.;.

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.14

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.79

T;T;T

M_CAP

Benign

0.0063

MetaRNN

Benign

0.19

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

M;.;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-1.5

N;.;N

REVEL

Benign

0.049

Sift

Benign

0.038

D;.;D

Sift4G

Benign

0.22

T;T;T

Polyphen

0.0060

B;.;P

Vest4

0.45

MVP

0.36

MPC

0.050

ClinPred

0.32

GERP RS

4.3

Varity_R

0.073

gMVP

0.39

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00017

dbscSNV1_RF

Benign

0.028

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over