Genetic Variant IFT81:p.Leu262Ser (chr12-110143385-T-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_014055.4(IFT81):c.785T>C(p.Leu262Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,240 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L262L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

IFT81
NM_014055.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.10

Publications

1 publications found

Variant links:

Genes affected

IFT81 (HGNC:14313): (intraflagellar transport 81) The protein encoded by this gene, together with IFT74, forms a tubulin-binding module of intraflagellar transport complex B. This module is involved in transport of tubulin within the cilium, and the encoded protein is required for ciliogenesis. Mutations in this gene are a cause of short-rib polydactyly syndromes. [provided by RefSeq, Dec 2016]

IFT81 Gene-Disease associations (from GenCC):

short-rib thoracic dysplasia 19 with or without polydactyly
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
ciliopathy
Inheritance: AR Classification: LIMITED Submitted by: Franklin by Genoox

IFT81 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IFT81	NM_014055.4 link	c.785T>C	p.Leu262Ser	missense_variant	Exon 9 of 19	ENST00000242591.10	NP_054774.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IFT81	ENST00000242591.10 link	c.785T>C	p.Leu262Ser	missense_variant	Exon 9 of 19	1	NM_014055.4	ENSP00000242591.5		Q8WYA0-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1169086

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

579398

African (AFR)

AF:

0.00

AC:

AN:

23966

American (AMR)

AF:

0.00

AC:

AN:

16986

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20478

East Asian (EAS)

AF:

0.00

AC:

AN:

30934

South Asian (SAS)

AF:

0.00

AC:

AN:

60328

European-Finnish (FIN)

AF:

0.00

AC:

AN:

43666

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3430

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

920822

Other (OTH)

AF:

0.00

AC:

AN:

48476

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41566

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10572

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68012

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.39

.;T;T;.

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.90

D;.;D;D

M_CAP

Benign

0.043

MetaRNN

Uncertain

0.46

T;T;T;T

MetaSVM

Benign

-0.77

MutationAssessor

Uncertain

2.5

M;M;M;.

PhyloP100

7.1

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-5.3

D;D;D;D

REVEL

Uncertain

0.35

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Uncertain

0.013

D;D;D;D

Polyphen

0.68

P;P;P;.

Vest4

0.93

MutPred

0.20

Gain of phosphorylation at L262 (P = 0.0085);Gain of phosphorylation at L262 (P = 0.0085);Gain of phosphorylation at L262 (P = 0.0085);.;

MVP

0.55

MPC

0.71

ClinPred

0.99

GERP RS

4.9

Varity_R

0.48

gMVP

0.64

Mutation Taster

=43/57

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over