Genetic Variant IFT88:p.Arg696Pro (chr13-20663516-G-C) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_006531.5(IFT88):c.2087G>C(p.Arg696Pro) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R696H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

IFT88
NM_006531.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity no assertion criteria provided P:1U:1

Conservation

PhyloP100: 6.35

Publications

3 publications found

Variant links:

Genes affected

IFT88 (HGNC:20606): (intraflagellar transport 88) This gene encodes a member of the tetratrico peptide repeat (TPR) family. The encoded protein is involved in cilium biogenesis. Mutations of a similar gene in mouse can cause polycystic kidney disease. Several transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2017]

IFT88 Gene-Disease associations (from GenCC):

retinitis pigmentosa
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

IFT88 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.868

PP5

Variant 13-20663516-G-C is Pathogenic according to our data. Variant chr13-20663516-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 446683.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006531.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IFT88	NM_006531.5	MANE Select	c.2087G>C	p.Arg696Pro	missense	Exon 23 of 26	NP_006522.2
IFT88	NM_001318493.2		c.2114G>C	p.Arg705Pro	missense	Exon 24 of 27	NP_001305422.1	Q13099-1
IFT88	NM_001353565.2		c.2114G>C	p.Arg705Pro	missense	Exon 24 of 27	NP_001340494.1	Q13099-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IFT88	ENST00000351808.10	TSL:1 MANE Select	c.2087G>C	p.Arg696Pro	missense	Exon 23 of 26	ENSP00000261632.5	Q13099-2
IFT88	ENST00000319980.10	TSL:1	c.2114G>C	p.Arg705Pro	missense	Exon 25 of 28	ENSP00000323580.6	Q13099-1
IFT88	ENST00000894242.1		c.2087G>C	p.Arg696Pro	missense	Exon 24 of 27	ENSP00000564301.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Jeune thoracic dystrophy (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.80

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

M_CAP

Benign

0.070

MetaRNN

Pathogenic

0.87

MetaSVM

Benign

-0.53

MutationAssessor

Pathogenic

3.0

PhyloP100

6.3

PrimateAI

Uncertain

0.79

PROVEAN

Pathogenic

-5.5

REVEL

Pathogenic

0.66

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.012

Polyphen

1.0

Vest4

0.86

MutPred

0.61

Gain of catalytic residue at L706 (P = 0.006)

MVP

0.60

MPC

0.31

ClinPred

1.0

GERP RS

5.8

Varity_R

0.91

gMVP

0.87

Mutation Taster

=33/67

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.26

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.26

Position offset: -18

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over