16-1587996-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.839G>A(p.Arg280Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00412 in 1,613,742 control chromosomes in the GnomAD database, including 222 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. R280W) has been classified as Benign.

Frequency

Genomes: 𝑓 0.020 ( 105 hom., cov: 32)

Exomes 𝑓: 0.0024 ( 117 hom. )

Consequence

IFT140
NM_014714.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.381

Publications

3 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=0.0040155947).

BP6

Variant 16-1587996-C-T is Benign according to our data. Variant chr16-1587996-C-T is described in ClinVar as Benign. ClinVar VariationId is 318201.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0675 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IFT140	NM_014714.4 link	c.839G>A	p.Arg280Gln	missense_variant	Exon 8 of 31	ENST00000426508.7	NP_055529.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
IFT140	ENST00000426508.7 link	c.839G>A	p.Arg280Gln	missense_variant	Exon 8 of 31	5	NM_014714.4	ENSP00000406012.2
IFT140	ENST00000439987.6 link	n.900G>A		non_coding_transcript_exon_variant	Exon 7 of 19	2
IFT140	ENST00000397417.6 link	n.329-3576G>A		intron_variant	Intron 3 of 23	5		ENSP00000380562.2
ENSG00000260989	ENST00000563162.1 link	n.59+7411C>T		intron_variant	Intron 1 of 2	2

Frequencies

GnomAD3 genomes

AF:

0.0204

AC:

3098

AN:

152126

Hom.:

105

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0698

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00890

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000559

Gnomad OTH

AF:

0.0148

GnomAD2 exomes

AF:

0.00563

AC:

1410

AN:

250604

AF XY:

0.00410

show subpopulations

Gnomad AFR exome

AF:

0.0718

Gnomad AMR exome

AF:

0.00464

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000324

Gnomad NFE exome

AF:

0.000494

Gnomad OTH exome

AF:

0.00475

GnomAD4 exome

AF:

0.00243

AC:

3549

AN:

1461498

Hom.:

117

Cov.:

AF XY:

0.00207

AC XY:

1506

AN XY:

727036

show subpopulations

African (AFR)

AF:

0.0739

AC:

2471

AN:

33450

American (AMR)

AF:

0.00492

AC:

220

AN:

44688

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26114

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.000279

AC:

AN:

86172

European-Finnish (FIN)

AF:

0.000356

AC:

AN:

53378

Middle Eastern (MID)

AF:

0.00364

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000436

AC:

485

AN:

1111856

Other (OTH)

AF:

0.00508

AC:

307

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

160

320

481

641

801

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

172

258

344

430

<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:

0.0203

AC:

3096

AN:

152244

Hom.:

105

Cov.:

AF XY:

0.0196

AC XY:

1461

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.0696

AC:

2889

AN:

41522

American (AMR)

AF:

0.00889

AC:

136

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000207

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.000189

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000544

AC:

AN:

68024

Other (OTH)

AF:

0.0147

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

142

284

427

569

711

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

150

<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:

0.00789

Hom.:

Bravo

AF:

0.0238

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.0680

AC:

299

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00652

AC:

792

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.000709

EpiControl

AF:

0.000415

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

May 04, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Saldino-Mainzer syndrome

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.78

CADD

Benign

0.044

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.0080

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.022

LIST_S2

Benign

0.53

MetaRNN

Benign

0.0040

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

PhyloP100

-0.38

PrimateAI

Benign

0.20

PROVEAN

Benign

-0.25

REVEL

Benign

0.056

Sift

Benign

0.14

Sift4G

Benign

0.62

Polyphen

0.0030

Vest4

0.081

MVP

0.072

MPC

0.078

ClinPred

0.0037

GERP RS

-11

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.016

gMVP

0.24

Mutation Taster

=96/4

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