Variant 11-118545421-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001168618.2(IFT46):c.807C>G(p.Phe269Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,459,504 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

IFT46
NM_001168618.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.61

Variant links:

Genes affected

IFT46 (HGNC:26146): (intraflagellar transport 46) Predicted to enable protein C-terminus binding activity. Predicted to be involved in cilium assembly; intraciliary transport; and protein stabilization. Predicted to act upstream of or within smoothened signaling pathway. Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

IFT46 links:

TMEM25 (HGNC:25890): (transmembrane protein 25) Predicted to be involved in negative regulation of excitatory postsynaptic potential and regulation of protein stability. Predicted to be located in late endosome and lysosome. [provided by Alliance of Genome Resources, Apr 2022]

TMEM25 links:

IFT46 (HGNC:):

IFT46 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.816

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IFT46	NM_001168618.2 linkuse as main transcript	c.807C>G	p.Phe269Leu	missense_variant	11/12	ENST00000264021.8	NP_001162089.1	Q9NQC8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IFT46	ENST00000264021.8 linkuse as main transcript	c.807C>G	p.Phe269Leu	missense_variant	11/12	1	NM_001168618.2	ENSP00000264021.3		Q9NQC8-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459504

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726268

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.01e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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

Mar 31, 2023

The c.960C>G (p.F320L) alteration is located in exon 12 (coding exon 10) of the IFT46 gene. This alteration results from a C to G substitution at nucleotide position 960, causing the phenylalanine (F) at amino acid position 320 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

0.98

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.060

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

T;.

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.81

T;T

M_CAP

Benign

0.034

MetaRNN

Pathogenic

0.82

D;D

MetaSVM

Benign

-0.56

MutationAssessor

Uncertain

2.5

M;.

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-5.6

D;D

REVEL

Uncertain

0.32

Sift

Benign

0.073

T;D

Sift4G

Benign

0.12

T;T

Polyphen

0.99

D;D

Vest4

0.71

MutPred

0.70

Loss of methylation at K270 (P = 0.0438);.;

MVP

0.28

MPC

0.76

ClinPred

0.99

GERP RS

5.1

Varity_R

0.42

gMVP

0.68

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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