chr16-1510954-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_014714.4(IFT140):ā€‹c.4379A>Gā€‹(p.Asp1460Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000683 in 1,611,504 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.000046 ( 0 hom., cov: 33)
Exomes š‘“: 0.0000027 ( 0 hom. )

Consequence

IFT140
NM_014714.4 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -0.305
Variant links:
Genes affected
IFT140 (HGNC:29077): (intraflagellar transport 140) This gene encodes one of the subunits of the intraflagellar transport (IFT) complex A. Intraflagellar transport is involved in the genesis, resorption and signaling of primary cilia. The primary cilium is a microtubule-based sensory organelle at the surface of most quiescent mammalian cells, that receives signals from its environment, such as the flow of fluid, light or odors, and transduces those signals to the nucleus. Loss of the corresponding protein in mouse results in renal cystic disease. [provided by RefSeq, Jun 2012]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.053654492).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
IFT140NM_014714.4 linkuse as main transcriptc.4379A>G p.Asp1460Gly missense_variant 31/31 ENST00000426508.7 NP_055529.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
IFT140ENST00000426508.7 linkuse as main transcriptc.4379A>G p.Asp1460Gly missense_variant 31/315 NM_014714.4 ENSP00000406012 P1Q96RY7-1
IFT140ENST00000361339.9 linkuse as main transcriptc.1961A>G p.Asp654Gly missense_variant 13/131 ENSP00000354895 Q96RY7-2
IFT140ENST00000565298.5 linkuse as main transcriptn.4203A>G non_coding_transcript_exon_variant 19/192
IFT140ENST00000397417.6 linkuse as main transcriptc.*2817A>G 3_prime_UTR_variant, NMD_transcript_variant 24/245 ENSP00000380562

Frequencies

GnomAD3 genomes
AF:
0.0000460
AC:
7
AN:
152226
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000169
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
GnomAD3 exomes
AF:
0.00000812
AC:
2
AN:
246298
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
133582
show subpopulations
Gnomad AFR exome
AF:
0.0000637
Gnomad AMR exome
AF:
0.0000292
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1459278
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
725724
show subpopulations
Gnomad4 AFR exome
AF:
0.0000898
Gnomad4 AMR exome
AF:
0.0000224
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000460
AC:
7
AN:
152226
Hom.:
0
Cov.:
33
AF XY:
0.0000538
AC XY:
4
AN XY:
74380
show subpopulations
Gnomad4 AFR
AF:
0.000169
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000378
ExAC
AF:
0.00000825
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Saldino-Mainzer syndrome;C4540439:Retinitis pigmentosa 80 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 18, 2021- -
Saldino-Mainzer syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 13, 2021Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0". The glycine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. This variant has not been reported in the literature in individuals affected with IFT140-related conditions. This variant is present in population databases (rs771632573, gnomAD 0.01%). This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 1460 of the IFT140 protein (p.Asp1460Gly). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.064
BayesDel_addAF
Benign
-0.35
T
BayesDel_noAF
Benign
-0.56
CADD
Benign
2.6
DANN
Benign
0.83
DEOGEN2
Benign
0.012
.;T
Eigen
Benign
-1.2
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.030
N
LIST_S2
Benign
0.50
T;T
M_CAP
Benign
0.011
T
MetaRNN
Benign
0.054
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.81
.;L
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.29
T
PROVEAN
Benign
-1.4
N;N
REVEL
Benign
0.046
Sift
Benign
0.082
T;T
Sift4G
Benign
0.18
T;T
Polyphen
0.0
.;B
Vest4
0.090
MutPred
0.10
.;Loss of solvent accessibility (P = 0.1177);
MVP
0.21
MPC
0.088
ClinPred
0.025
T
GERP RS
-1.5
Varity_R
0.056
gMVP
0.24

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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: rs771632573; hg19: chr16-1560955; API