16-1568305-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_014714.4(IFT140):c.1682G>A(p.Ser561Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00458 in 1,613,808 control chromosomes in the GnomAD database, including 289 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S561I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.025 ( 153 hom., cov: 32)

Exomes 𝑓: 0.0025 ( 136 hom. )

Consequence

IFT140
NM_014714.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.0950

Publications

9 publications found

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]

IFT140 Gene-Disease associations (from GenCC):

autosomal dominant polycystic kidney disease
Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics, ClinGen
IFT140-related recessive ciliopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, Illumina
short-rib thoracic dysplasia 9 with or without polydactyly
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
retinitis pigmentosa 80
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
Leber congenital amaurosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
retinitis pigmentosa
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Jeune syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

IFT140 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002524197).

BP6

Variant 16-1568305-C-T is Benign according to our data. Variant chr16-1568305-C-T is described in ClinVar as Benign. ClinVar VariationId is 318188.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0834 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IFT140	NM_014714.4 link	c.1682G>A	p.Ser561Asn	missense_variant	Exon 15 of 31	ENST00000426508.7	NP_055529.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IFT140	ENST00000426508.7 link	c.1682G>A	p.Ser561Asn	missense_variant	Exon 15 of 31	5	NM_014714.4	ENSP00000406012.2

Frequencies

GnomAD3 genomes

AF:

0.0244

AC:

3718

AN:

152188

Hom.:

152

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0856

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00746

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000412

Gnomad OTH

AF:

0.0134

GnomAD2 exomes

AF:

0.00650

AC:

1630

AN:

250586

AF XY:

0.00506

show subpopulations

Gnomad AFR exome

AF:

0.0893

Gnomad AMR exome

AF:

0.00353

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000256

Gnomad OTH exome

AF:

0.00311

GnomAD4 exome

AF:

0.00250

AC:

3652

AN:

1461502

Hom.:

136

Cov.:

AF XY:

0.00222

AC XY:

1612

AN XY:

727078

show subpopulations

African (AFR)

AF:

0.0881

AC:

2949

AN:

33472

American (AMR)

AF:

0.00407

AC:

182

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000522

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53086

Middle Eastern (MID)

AF:

0.00520

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000109

AC:

121

AN:

1111988

Other (OTH)

AF:

0.00538

AC:

325

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

175

350

524

699

874

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

188

282

376

470

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0245

AC:

3736

AN:

152306

Hom.:

153

Cov.:

AF XY:

0.0235

AC XY:

1752

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.0858

AC:

3563

AN:

41548

American (AMR)

AF:

0.00745

AC:

114

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.000414

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000412

AC:

AN:

68032

Other (OTH)

AF:

0.0133

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

174

348

523

697

871

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

160

200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00871

Hom.:

130

Bravo

AF:

0.0272

ESP6500AA

AF:

0.0894

AC:

393

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00780

AC:

947

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000474

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 05, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Saldino-Mainzer syndrome

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.64

CADD

Benign

0.23

(source)

DANN

Benign

0.20

DEOGEN2

Benign

0.0062

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.47

MetaRNN

Benign

0.0025

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-1.1

PhyloP100

0.095

PrimateAI

Benign

0.33

PROVEAN

Benign

1.1

REVEL

Benign

0.098

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.038

MVP

0.38

MPC

0.064

ClinPred

0.0021

GERP RS

-5.0

Varity_R

0.021

gMVP

0.10

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over