rs150370681

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_020800.3(IFT80):c.1883G>A(p.Arg628Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000433 in 1,613,656 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00044 ( 0 hom. )

Consequence

IFT80
NM_020800.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 1.46

Publications

5 publications found

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:

TRIM59-IFT80 (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]

TRIM59-IFT80 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.027761996).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020800.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
IFT80	NM_020800.3	MANE Select	c.1883G>A	p.Arg628Gln	missense	Exon 17 of 20	NP_065851.1
IFT80	NM_001190241.2		c.1472G>A	p.Arg491Gln	missense	Exon 18 of 21	NP_001177170.1
IFT80	NM_001190242.2		c.1472G>A	p.Arg491Gln	missense	Exon 16 of 19	NP_001177171.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
IFT80	ENST00000326448.12	TSL:1 MANE Select	c.1883G>A	p.Arg628Gln	missense	Exon 17 of 20	ENSP00000312778.7
IFT80	ENST00000483465.5	TSL:1	c.1472G>A	p.Arg491Gln	missense	Exon 16 of 19	ENSP00000418196.1
TRIM59-IFT80	ENST00000483754.1	TSL:2	n.2396G>A		non_coding_transcript_exon	Exon 15 of 19	ENSP00000456272.1

Frequencies

GnomAD3 genomes

AF:

0.000388

AC:

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

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:

0.000470

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.000355

AC:

AN:

250436

AF XY:

0.000347

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000695

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.000487

Gnomad OTH exome

AF:

0.000820

GnomAD4 exome

AF:

0.000438

AC:

640

AN:

1461418

Hom.:

Cov.:

AF XY:

0.000447

AC XY:

325

AN XY:

726998

show subpopulations

African (AFR)

AF:

0.0000897

AC:

AN:

33454

American (AMR)

AF:

0.000716

AC:

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.000153

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39640

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86236

European-Finnish (FIN)

AF:

0.0000562

AC:

AN:

53370

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000509

AC:

566

AN:

1111766

Other (OTH)

AF:

0.000480

AC:

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

102

136

170

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

<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:

0.000388

AC:

AN:

152238

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41534

American (AMR)

AF:

0.00118

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000470

AC:

AN:

68016

Other (OTH)

AF:

0.00142

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000499

Hom.:

Bravo

AF:

0.000582

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000321

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000652

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Asphyxiating thoracic dystrophy 2

Uncertain:3

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 09, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

not provided

Uncertain:2

Apr 29, 2019

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge

Feb 06, 2015

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jeune thoracic dystrophy

Uncertain:1

Oct 24, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 628 of the IFT80 protein (p.Arg628Gln). This variant is present in population databases (rs150370681, gnomAD 0.07%). This variant has not been reported in the literature in individuals affected with IFT80-related conditions. ClinVar contains an entry for this variant (Variation ID: 194779). 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 not expected to disrupt IFT80 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.17

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.016

MetaRNN

Benign

0.028

MetaSVM

Benign

-0.72

MutationAssessor

Benign

1.3

PhyloP100

1.5

PrimateAI

Benign

0.25

PROVEAN

Benign

-1.7

REVEL

Benign

0.25

Sift

Benign

0.18

Sift4G

Benign

0.25

Polyphen

0.0010

Vest4

0.12

MVP

0.82

MPC

0.18

ClinPred

0.032

GERP RS

1.9

Varity_R

0.089

gMVP

0.30

Mutation Taster

=92/8

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over