chr3-108162648-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_018010.4(IFT57):​c.1119G>T​(p.Leu373Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000203 in 1,594,838 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 (★★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00021 ( 0 hom. )

Consequence

IFT57
NM_018010.4 missense

Scores

3
11
5

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.944
Variant links:
Genes affected
IFT57 (HGNC:17367): (intraflagellar transport 57) Predicted to enable DNA binding activity. Acts upstream of or within activation of cysteine-type endopeptidase activity involved in apoptotic process; apoptotic process; and regulation of apoptotic process. Predicted to be located in ciliary basal body. Predicted to be part of axoneme and intraciliary transport particle B. Predicted to be active in Golgi apparatus; centrosome; and cilium. Implicated in orofaciodigital syndrome. [provided by Alliance of Genome Resources, Apr 2022]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.3783087).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
IFT57NM_018010.4 linkuse as main transcriptc.1119G>T p.Leu373Phe missense_variant 11/11 ENST00000264538.4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
IFT57ENST00000264538.4 linkuse as main transcriptc.1119G>T p.Leu373Phe missense_variant 11/111 NM_018010.4 P1

Frequencies

GnomAD3 genomes
AF:
0.000164
AC:
25
AN:
152120
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
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:
0.000309
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000151
AC:
36
AN:
238334
Hom.:
0
AF XY:
0.000132
AC XY:
17
AN XY:
128980
show subpopulations
Gnomad AFR exome
AF:
0.0000627
Gnomad AMR exome
AF:
0.0000947
Gnomad ASJ exome
AF:
0.000210
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000234
Gnomad NFE exome
AF:
0.000222
Gnomad OTH exome
AF:
0.000173
GnomAD4 exome
AF:
0.000207
AC:
298
AN:
1442600
Hom.:
0
Cov.:
29
AF XY:
0.000193
AC XY:
138
AN XY:
716606
show subpopulations
Gnomad4 AFR exome
AF:
0.0000306
Gnomad4 AMR exome
AF:
0.000119
Gnomad4 ASJ exome
AF:
0.0000788
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000944
Gnomad4 NFE exome
AF:
0.000254
Gnomad4 OTH exome
AF:
0.0000672
GnomAD4 genome
AF:
0.000164
AC:
25
AN:
152238
Hom.:
0
Cov.:
32
AF XY:
0.000161
AC XY:
12
AN XY:
74434
show subpopulations
Gnomad4 AFR
AF:
0.0000481
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000309
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000209
Hom.:
1
Bravo
AF:
0.000121
TwinsUK
AF:
0.000539
AC:
2
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.000206
AC:
25

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 22, 2023This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 373 of the IFT57 protein (p.Leu373Phe). This variant is present in population databases (rs200995912, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with IFT57-related conditions. ClinVar contains an entry for this variant (Variation ID: 1496622). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -
Uncertain significance, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMay 04, 2023The c.1119G>T (p.L373F) alteration is located in exon 11 (coding exon 11) of the IFT57 gene. This alteration results from a G to T substitution at nucleotide position 1119, causing the leucine (L) at amino acid position 373 to be replaced by a phenylalanine (F). 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
Uncertain
0.50
BayesDel_addAF
Benign
-0.14
T
BayesDel_noAF
Benign
-0.14
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.85
D
Eigen
Pathogenic
0.75
Eigen_PC
Pathogenic
0.71
FATHMM_MKL
Uncertain
0.85
D
LIST_S2
Uncertain
0.93
D
M_CAP
Benign
0.016
T
MetaRNN
Benign
0.38
T
MetaSVM
Uncertain
-0.068
T
MutationAssessor
Uncertain
2.4
M
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.53
T
PROVEAN
Uncertain
-3.2
D
REVEL
Uncertain
0.38
Sift
Uncertain
0.0070
D
Sift4G
Uncertain
0.011
D
Polyphen
1.0
D
Vest4
0.41
MutPred
0.75
Gain of methylation at K375 (P = 0.0971);
MVP
0.85
MPC
0.81
ClinPred
0.24
T
GERP RS
5.9
Varity_R
0.24
gMVP
0.28

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: rs200995912; hg19: chr3-107881495; API