rs138004478

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBS1_Supporting

The NM_020800.3(IFT80):c.721G>C(p.Gly241Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000731 in 1,614,156 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00040 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000039 ( 0 hom. )

Consequence

IFT80
NM_020800.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7U:1

Conservation

PhyloP100: 7.57

Variant links:

Genes affected

IFT80 (HGNC:29262): (intraflagellar transport 80) The protein encoded by this gene is part of the intraflagellar transport complex B and is necessary for the function of motile and sensory cilia. Defects in this gene are a cause of asphyxiating thoracic dystrophy 2 (ATD2). Three transcript variants encoding two different isoforms have been found for this gene.[provided by RefSeq, Jun 2010]

IFT80 links:

ENSG00000248710 (HGNC:56756): (TRIM59-IFT80 readthrough (NMD candidate)) This locus represents naturally occurring readthrough transcription between the neighboring TRIM59 (tripartite motif containing 59) and IFT80 (intraflagellar transport 80) genes on chromosome 3. The readthrough transcript is unlikely to produce a protein product. [provided by RefSeq, Jun 2017]

ENSG00000248710 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 3-160356069-C-G is Pathogenic according to our data. Variant chr3-160356069-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 406218.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-160356069-C-G is described in Lovd as [Likely_pathogenic].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0004 (61/152336) while in subpopulation AFR AF= 0.00142 (59/41570). AF 95% confidence interval is 0.00113. There are 0 homozygotes in gnomad4. There are 22 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IFT80	NM_020800.3 link	c.721G>C	p.Gly241Arg	missense_variant	8/20	ENST00000326448.12	NP_065851.1	Q9P2H3-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IFT80	ENST00000326448.12 link	c.721G>C	p.Gly241Arg	missense_variant	8/20	1	NM_020800.3	ENSP00000312778.7		Q9P2H3-1
ENSG00000248710	ENST00000483754.1 link	n.1234G>C		non_coding_transcript_exon_variant	6/19	2		ENSP00000456272.1		H3BRJ5

Frequencies

GnomAD3 genomes

AF:

0.000401

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00142

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000676

AC:

AN:

251404

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135866

show subpopulations

Gnomad AFR exome

AF:

0.000738

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000390

AC:

AN:

1461820

Hom.:

Cov.:

AF XY:

0.0000344

AC XY:

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.00134

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.000400

AC:

AN:

152336

Hom.:

Cov.:

AF XY:

0.000295

AC XY:

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.00142

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:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000729

Hom.:

Bravo

AF:

0.000431

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000906

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Jeune thoracic dystrophy

Pathogenic:3

Likely pathogenic, no assertion criteria provided	research	University of Washington Center for Mendelian Genomics, University of Washington	-	- -
Pathogenic, no assertion criteria provided	research	Dan Cohn Lab, University Of California Los Angeles	Jun 01, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 11, 2023	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 241 of the IFT80 protein (p.Gly241Arg). This variant is present in population databases (rs138004478, gnomAD 0.1%). This missense change has been observed in individuals with short-rib thoracic dysplasia (PMID: 19648123, 29068549, 30266093). ClinVar contains an entry for this variant (Variation ID: 406218). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt IFT80 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Short-rib thoracic dysplasia 6 with or without polydactyly

Pathogenic:2

Likely pathogenic, no assertion criteria provided	research	University of Washington Center for Mendelian Genomics, University of Washington	-	- -
Pathogenic, no assertion criteria provided	research	Dan Cohn Lab, University Of California Los Angeles	Jun 01, 2017	- -

Asphyxiating thoracic dystrophy 2

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jun 01, 2023

The IFT80 c.721G>C; p.Gly241Arg variant (rs138004478) is reported in the literature in the homozygous or compound heterozygous state in individuals affected with short-rib thoracic dysplasia II, asphyxiating thoracic dystrophy, or Jeune-Verma-Naumoff dysplasia (Cavalcanti 2011, Normand 2018, Zhang 2018). This variant is also reported in ClinVar (Variation ID: 406218), and is found in the African/African-American population with an allele frequency of 0.12% (30/24974 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.628). Based on available information, this variant is considered to be likely pathogenic. References: Cavalcanti D et al. Mutation in IFT80 in a fetus with the phenotype of Verma-Naumoff provides molecular evidence for Jeune-Verma-Naumoff dysplasia spectrum. J Med Genet. 2011; 48(2):88-92. PMID: 19648123. Normand EA et al. Clinical exome sequencing for fetuses with ultrasound abnormalities and a suspected Mendelian disorder. Genome Med. 2018 Sep 28;10(1):74. PMID: 30266093. Zhang W et al. Expanding the genetic architecture and phenotypic spectrum in the skeletal ciliopathies. Hum Mutat. 2018 Jan;39(1):152-166. PMID: 29068549. -

IFT80-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 08, 2024

The IFT80 c.721G>C variant is predicted to result in the amino acid substitution p.Gly241Arg. This variant was reported in the homozygous state in multiple individuals with short-rib thoracic dysplasia (Cavalcanti et al. 2011. PubMed ID: 19648123; Zhang et al. 2017. PubMed ID: 29068549; Normand et al. 2018. PubMed ID: 30266093). This variant is reported in 0.12% of alleles in individuals of African descent in gnomAD. This variant is interpreted as pathogenic. -

not provided

Uncertain:1

Uncertain significance, flagged submission

clinical testing

Eurofins Ntd Llc (ga)

Mar 02, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Benign

0.0021

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.65

D;.;.;T

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;.;D;D

M_CAP

Uncertain

0.10

MetaRNN

Uncertain

0.57

D;D;D;D

MetaSVM

Uncertain

-0.11

MutationAssessor

Pathogenic

4.4

H;.;.;.

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-7.4

D;D;D;D

REVEL

Uncertain

0.63

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Uncertain

0.0020

D;D;D;D

Polyphen

1.0

D;.;.;.

Vest4

0.98

MutPred

0.88

Gain of sheet (P = 0.1208);.;.;.;

MVP

0.81

MPC

0.73

ClinPred

1.0

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.82

gMVP

0.76

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.

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