16-1587999-C-G

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.836G>C(p.Arg279Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0443 in 1,613,380 control chromosomes in the GnomAD database, including 2,167 homozygotes. 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R279H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.043 ( 248 hom., cov: 32)

Exomes 𝑓: 0.044 ( 1919 hom. )

Consequence

IFT140
NM_014714.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.279

Publications

12 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:

ENSG00000260989 (HGNC:):

ENSG00000260989 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=0.0017949343).

BP6

Variant 16-1587999-C-G is Benign according to our data. Variant chr16-1587999-C-G is described in ClinVar as Benign. ClinVar VariationId is 129262.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.074 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IFT140	NM_014714.4 link	c.836G>C	p.Arg279Pro	missense_variant	Exon 8 of 31	ENST00000426508.7	NP_055529.2	Q96RY7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
IFT140	ENST00000426508.7 link	c.836G>C	p.Arg279Pro	missense_variant	Exon 8 of 31	5	NM_014714.4	ENSP00000406012.2	Q96RY7-1
IFT140	ENST00000439987.6 link	n.897G>C		non_coding_transcript_exon_variant	Exon 7 of 19	2
IFT140	ENST00000397417.6 link	n.329-3579G>C		intron_variant	Intron 3 of 23	5		ENSP00000380562.2	J3KPW0
ENSG00000260989	ENST00000563162.1 link	n.59+7414C>G		intron_variant	Intron 1 of 2	2

Frequencies

GnomAD3 genomes

AF:

0.0425

AC:

6471

AN:

152122

Hom.:

248

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00900

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.0772

Gnomad ASJ

AF:

0.0179

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0139

Gnomad FIN

AF:

0.141

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0472

Gnomad OTH

AF:

0.0340

GnomAD2 exomes

AF:

0.0500

AC:

12510

AN:

250286

AF XY:

0.0471

show subpopulations

Gnomad AFR exome

AF:

0.00754

Gnomad AMR exome

AF:

0.102

Gnomad ASJ exome

AF:

0.0142

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.133

Gnomad NFE exome

AF:

0.0448

Gnomad OTH exome

AF:

0.0487

GnomAD4 exome

AF:

0.0444

AC:

64918

AN:

1461140

Hom.:

1919

Cov.:

AF XY:

0.0437

AC XY:

31772

AN XY:

726864

show subpopulations

African (AFR)

AF:

0.00753

AC:

252

AN:

33462

American (AMR)

AF:

0.104

AC:

4653

AN:

44608

Ashkenazi Jewish (ASJ)

AF:

0.0155

AC:

405

AN:

26108

East Asian (EAS)

AF:

0.000227

AC:

AN:

39692

South Asian (SAS)

AF:

0.0166

AC:

1432

AN:

86156

European-Finnish (FIN)

AF:

0.128

AC:

6804

AN:

53316

Middle Eastern (MID)

AF:

0.00798

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0440

AC:

48925

AN:

1111660

Other (OTH)

AF:

0.0396

AC:

2392

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

2933

5866

8800

11733

14666

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1808

3616

5424

7232

9040

<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:

0.0426

AC:

6480

AN:

152240

Hom.:

248

Cov.:

AF XY:

0.0462

AC XY:

3442

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.00900

AC:

374

AN:

41556

American (AMR)

AF:

0.0777

AC:

1188

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0179

AC:

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5182

South Asian (SAS)

AF:

0.0141

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.141

AC:

1498

AN:

10588

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0472

AC:

3210

AN:

68016

Other (OTH)

AF:

0.0336

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

317

634

952

1269

1586

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

156

234

312

390

<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:

0.0250

Hom.:

Bravo

AF:

0.0361

TwinsUK

AF:

0.0415

AC:

154

ALSPAC

AF:

0.0397

AC:

153

ESP6500AA

AF:

0.00773

AC:

ESP6500EA

AF:

0.0442

AC:

380

ExAC

AF:

0.0452

AC:

5492

Asia WGS

AF:

0.00924

AC:

AN:

3478

EpiCase

AF:

0.0406

EpiControl

AF:

0.0380

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Saldino-Mainzer syndrome

Benign:4

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. -

Jan 12, 2016

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Apr 06, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.67

CADD

Benign

0.16

(source)

DANN

Benign

0.71

DEOGEN2

Benign

0.0036

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.059

LIST_S2

Benign

0.58

MetaRNN

Benign

0.0018

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

PhyloP100

-0.28

PrimateAI

Benign

0.20

PROVEAN

Benign

0.11

REVEL

Benign

0.036

Sift

Benign

0.34

Sift4G

Benign

0.35

Polyphen

0.0

Vest4

0.077

MPC

0.097

ClinPred

0.010

GERP RS

-11

Varity_R

0.079

gMVP

0.49

Mutation Taster

=95/5

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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