rs746697405

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP3BS1_SupportingBS2

The NM_014714.4(IFT140):c.3955_3960delGCCAAG(p.Ala1319_Lys1320del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00205 in 1,607,122 control chromosomes in the GnomAD database, including 8 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0013 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0021 ( 7 hom. )

Consequence

IFT140
NM_014714.4 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:9B:1

Conservation

PhyloP100: 2.37

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_014714.4

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00212 (3086/1454760) while in subpopulation NFE AF= 0.00253 (2804/1109372). AF 95% confidence interval is 0.00245. There are 7 homozygotes in gnomad4_exome. There are 1508 alleles in male gnomad4_exome subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IFT140	NM_014714.4 link	c.3955_3960delGCCAAG	p.Ala1319_Lys1320del	conservative_inframe_deletion	Exon 29 of 31	ENST00000426508.7	NP_055529.2	Q96RY7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IFT140	ENST00000426508.7 link	c.3955_3960delGCCAAG	p.Ala1319_Lys1320del	conservative_inframe_deletion	Exon 29 of 31	5	NM_014714.4	ENSP00000406012.2		Q96RY7-1

Frequencies

GnomAD3 genomes

AF:

0.00133

AC:

203

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000675

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.000916

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00222

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00109

AC:

267

AN:

244378

Hom.:

AF XY:

0.00111

AC XY:

147

AN XY:

132404

show subpopulations

Gnomad AFR exome

AF:

0.000684

Gnomad AMR exome

AF:

0.000757

Gnomad ASJ exome

AF:

0.00356

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000337

Gnomad FIN exome

AF:

0.0000944

Gnomad NFE exome

AF:

0.00169

Gnomad OTH exome

AF:

0.00102

GnomAD4 exome

AF:

0.00212

AC:

3086

AN:

1454760

Hom.:

AF XY:

0.00208

AC XY:

1508

AN XY:

723680

show subpopulations

Gnomad4 AFR exome

AF:

0.000637

Gnomad4 AMR exome

AF:

0.000814

Gnomad4 ASJ exome

AF:

0.00316

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000586

Gnomad4 FIN exome

AF:

0.000283

Gnomad4 NFE exome

AF:

0.00253

Gnomad4 OTH exome

AF:

0.00200

GnomAD4 genome

AF:

0.00133

AC:

203

AN:

152362

Hom.:

Cov.:

AF XY:

0.00119

AC XY:

AN XY:

74516

show subpopulations

Gnomad4 AFR

AF:

0.000673

Gnomad4 AMR

AF:

0.000914

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00222

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000838

Hom.:

Bravo

AF:

0.00135

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:9Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

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

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Saldino-Mainzer syndrome

Uncertain:2Benign:1

Apr 04, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Orofacial-digital syndrome III;C4551856:Asphyxiating thoracic dystrophy 1

Pathogenic:1

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

not specified

Uncertain:1

Dec 18, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: IFT140 c.3955_3960delGCCAAG (p.Ala1319_Lys1320del) results in an in-frame deletion that is predicted to remove two amino acids from the encoded protein. The variant allele was found at a frequency of 0.002 in 1607122 control chromosomes in the gnomAD database, including 8 homozygotes, providing evidence for a benign role. However, c.3955_3960delGCCAAG has been reported in the literature in a homozygous stillborn individual affected with Jeune Asphyxiating Thoracic Dystrophy (e.g. Shaheen_2016, Shamseldin_2021) or in individuals affected with retinitis pigmentosa or an unspecified retinal disease as a heterozygous or unreported genotype (e.g. Sergouniotis_2016, AlBdour_2020, Perea-Romero_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Asphyxiating Thoracic Dystrophy 1. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32587456, 34448047, 27628848, 27894351, 34645488). ClinVar contains an entry for this variant (Variation ID: 266103). Based on the conflicting evidence outlined above, the variant was classified as uncertain significance. -

Inborn genetic diseases

Uncertain:1

Dec 12, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3955_3960delGCCAAG (p.A1319_K1320del) alteration is located in exon 29 (coding exon 27) of the IFT140 gene. This alteration consists of an in-frame deletion of 6 nucleotides between nucleotide positions c.3955 and c.3960, resulting in the deletion of 2 residues. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

IFT140-related disorder

Uncertain:1

Apr 04, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The IFT140 c.3955_3960del6 variant is predicted to result in an in-frame deletion (p.Ala1319_Lys1320del). This variant was reported in the homozygous state in an individual with short-rib thoracic dysplasia/oral-facial-digital syndrome (Patient 12DG1103, Table S3, Shaheen et al. 2016. PubMed ID: 27894351; Table S1, Shamseldin et al. 2021. PubMed ID: 34645488). This variant is reported in 0.36% of alleles in individuals of Ashkenazi Jewish descent in gnomAD, including one homozygote. This variant has been reported in ClinVar with conflicting interpretations of likely pathogenic (1), uncertain (4), and benign (1) (https://www.ncbi.nlm.nih.gov/clinvar/variation/266103/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Retinal dystrophy

Uncertain:1

Jan 01, 2023

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over