rs431905497

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PM4_SupportingPP5_Moderate

The NM_020800.3(IFT80):c.1646_1648delTAT(p.Leu549del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000685 in 1,459,910 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. L549L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

IFT80
NM_020800.3 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 8.63

Publications

1 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: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_020800.3. Strenght limited to Supporting due to length of the change: 1aa.

PP5

Variant 3-160280682-TATA-T is Pathogenic according to our data. Variant chr3-160280682-TATA-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 429428.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IFT80	NM_020800.3 link	c.1646_1648delTAT	p.Leu549del	disruptive_inframe_deletion	Exon 15 of 20	ENST00000326448.12	NP_065851.1	Q9P2H3-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IFT80	ENST00000326448.12 link	c.1646_1648delTAT	p.Leu549del	disruptive_inframe_deletion	Exon 15 of 20	1	NM_020800.3	ENSP00000312778.7		Q9P2H3-1
TRIM59-IFT80	ENST00000483754.1 link	n.2159_2161delTAT		non_coding_transcript_exon_variant	Exon 13 of 19	2		ENSP00000456272.1		H3BRJ5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

250978

AF XY:

0.00000737

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

0.00000685

AC:

AN:

1459910

Hom.:

AF XY:

0.0000138

AC XY:

AN XY:

726402

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33418

American (AMR)

AF:

0.00

AC:

AN:

44676

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26114

East Asian (EAS)

AF:

0.00

AC:

AN:

39584

South Asian (SAS)

AF:

0.000104

AC:

AN:

86200

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53270

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110576

Other (OTH)

AF:

0.00

AC:

AN:

60310

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Asphyxiating thoracic dystrophy 2

Pathogenic:1

Jun 01, 2007

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Pathogenic:1

May 09, 2017

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1646_1648delTAT variant in the IFT80 gene has been reported previously in the homozygous state in a stillborn with Jeune asphyxiating thoracic dystrophy (Beales et al., 2007). The c.1646_1648delTAT variant causes an in-frame deletion of codon Leucine 549, denoted p.Leu549del. The c.1646_1648delTAT variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.1646_1648delTAT as a likely pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

8.6

Mutation Taster

=70/30

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over