13-20574386-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PVS1_SupportingPM2

The NM_006531.5(IFT88):ā€‹c.1A>Gā€‹(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.0000598 in 1,606,362 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000098 ( 0 hom., cov: 32)
Exomes š‘“: 0.000056 ( 0 hom. )

Consequence

IFT88
NM_006531.5 start_lost

Scores

2
8
7

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.62
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PVS1
Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 3 CDS bases. Genomic position: 20574388. Lost 0.001 part of the original CDS.
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
IFT88NM_006531.5 linkc.1A>G p.Met1? start_lost Exon 2 of 26 ENST00000351808.10 NP_006522.2 Q13099-2A0A140VJL7B3KX42

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
IFT88ENST00000351808.10 linkc.1A>G p.Met1? start_lost Exon 2 of 26 1 NM_006531.5 ENSP00000261632.5 Q13099-2
IFT88ENST00000319980.10 linkc.28A>G p.Met10Val missense_variant Exon 4 of 28 1 ENSP00000323580.6 Q13099-1
IFT88ENST00000389373.3 linkc.1A>G p.Met1? start_lost Exon 3 of 4 4 ENSP00000374024.3 F6SRW8

Frequencies

GnomAD3 genomes
AF:
0.0000985
AC:
15
AN:
152232
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.00141
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000152
AC:
38
AN:
249890
Hom.:
0
AF XY:
0.000155
AC XY:
21
AN XY:
135130
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:
0.00139
Gnomad NFE exome
AF:
0.0000618
Gnomad OTH exome
AF:
0.000165
GnomAD4 exome
AF:
0.0000557
AC:
81
AN:
1454012
Hom.:
0
Cov.:
28
AF XY:
0.0000608
AC XY:
44
AN XY:
723634
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:
0.00132
Gnomad4 NFE exome
AF:
0.00000723
Gnomad4 OTH exome
AF:
0.0000499
GnomAD4 genome
AF:
0.0000985
AC:
15
AN:
152350
Hom.:
0
Cov.:
32
AF XY:
0.000161
AC XY:
12
AN XY:
74512
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00141
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000547
Hom.:
0
Bravo
AF:
0.00000378
ExAC
AF:
0.0000988
AC:
12

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Nov 11, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 10 of the IFT88 protein (p.Met10Val). This variant is present in population databases (rs191277814, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with IFT88-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
0.087
D
BayesDel_noAF
Uncertain
0.070
CADD
Benign
23
DANN
Uncertain
0.99
DEOGEN2
Benign
0.14
.;T;.
Eigen
Benign
0.030
Eigen_PC
Benign
0.21
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.90
D;T;D
M_CAP
Benign
0.068
D
MetaRNN
Benign
0.10
T;T;T
MetaSVM
Uncertain
-0.0047
T
MutationAssessor
Uncertain
2.2
.;M;.
PROVEAN
Benign
-0.73
N;N;N
REVEL
Uncertain
0.48
Sift
Uncertain
0.013
D;D;D
Sift4G
Pathogenic
0.0
D;T;D
Polyphen
0.034
.;B;.
Vest4
0.82
MVP
0.80
MPC
0.077
ClinPred
0.12
T
GERP RS
5.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.18
gMVP
0.21

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.060
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.

Other links and lift over

dbSNP: rs191277814; hg19: chr13-21148525; API