6-167003779-A-T

Position:

• chr6-167003779-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_007045.4(CEP43):​c.268A>T​(p.Thr90Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CEP43 NM_007045.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.86

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.941

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CEP43	NM_007045.4	c.268A>T	p.Thr90Ser	missense_variant	4/13	ENST00000366847.9
CEP43	NM_194429.3	c.268A>T	p.Thr90Ser	missense_variant	4/12
CEP43	NM_001278690.2	c.268A>T	p.Thr90Ser	missense_variant	4/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEP43	ENST00000366847.9	c.268A>T	p.Thr90Ser	missense_variant	4/13	1	NM_007045.4	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 33

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

May 09, 2022

The c.268A>T (p.T90S) alteration is located in exon 4 (coding exon 4) of the FGFR1OP gene. This alteration results from a A to T substitution at nucleotide position 268, causing the threonine (T) at amino acid position 90 to be replaced by a serine (S). 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	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	T;.;.
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Benign	0.0059	T
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	0.95	L;.;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.8	D;.;D
REVEL	Uncertain	0.33
Sift	Benign	0.078	T;.;T
Sift4G	Benign	0.13	T;T;T
Polyphen		0.99	D;.;D
Vest4		0.89
MutPred		0.85		Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);
MVP		0.75
MPC		0.28
ClinPred		0.98	D
GERP RS		6.1
Varity_R		0.72
gMVP		0.56

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-167417267;