dbSNP rs144099135: IFT80:p.Ser359Phe (chr3-160307663-G-A) – ACMG Classification: Benign (-15 pts)

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3BP6_Very_StrongBS1BS2

The NM_020800.3(IFT80):c.1076C>T(p.Ser359Phe) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00809 in 1,445,354 control chromosomes in the GnomAD database, including 99 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0076 ( 9 hom., cov: 32)

Exomes 𝑓: 0.0081 ( 90 hom. )

Consequence

IFT80
NM_020800.3 missense, splice_region

Scores

Splicing: ADA: 0.9923

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 4.50

Publications

17 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: Benign. The variant received -15 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

BP6

Variant 3-160307663-G-A is Benign according to our data. Variant chr3-160307663-G-A is described in ClinVar as Benign. ClinVar VariationId is 193733.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00764 (1163/152250) while in subpopulation AMR AF = 0.0243 (372/15280). AF 95% confidence interval is 0.0223. There are 9 homozygotes in GnomAd4. There are 569 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 9 AR gene

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	UniProt
IFT80	NM_020800.3	MANE Select	c.1076C>T	p.Ser359Phe	missense splice_region	Exon 10 of 20	NP_065851.1	Q9P2H3-1
IFT80	NM_001190241.2		c.665C>T	p.Ser222Phe	missense splice_region	Exon 11 of 21	NP_001177170.1	Q9P2H3-2
IFT80	NM_001190242.2		c.665C>T	p.Ser222Phe	missense splice_region	Exon 9 of 19	NP_001177171.1	Q9P2H3-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IFT80	ENST00000326448.12	TSL:1 MANE Select	c.1076C>T	p.Ser359Phe	missense splice_region	Exon 10 of 20	ENSP00000312778.7	Q9P2H3-1
IFT80	ENST00000483465.5	TSL:1	c.665C>T	p.Ser222Phe	missense splice_region	Exon 9 of 19	ENSP00000418196.1	Q9P2H3-2
TRIM59-IFT80	ENST00000483754.1	TSL:2	n.1589C>T		splice_region non_coding_transcript_exon	Exon 8 of 19	ENSP00000456272.1	H3BRJ5

Frequencies

GnomAD3 genomes

AF:

0.00762

AC:

1159

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00381

Gnomad AMI

AF:

0.0451

Gnomad AMR

AF:

0.0240

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000771

Gnomad SAS

AF:

0.00435

Gnomad FIN

AF:

0.00481

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00737

Gnomad OTH

AF:

0.00671

GnomAD2 exomes

AF:

0.0108

AC:

2703

AN:

250732

AF XY:

0.00914

show subpopulations

Gnomad AFR exome

AF:

0.00425

Gnomad AMR exome

AF:

0.0436

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.00136

Gnomad FIN exome

AF:

0.00505

Gnomad NFE exome

AF:

0.00709

Gnomad OTH exome

AF:

0.00914

GnomAD4 exome

AF:

0.00814

AC:

10527

AN:

1293104

Hom.:

Cov.:

AF XY:

0.00770

AC XY:

5024

AN XY:

652494

show subpopulations

African (AFR)

AF:

0.00272

AC:

AN:

30108

American (AMR)

AF:

0.0424

AC:

1887

AN:

44504

Ashkenazi Jewish (ASJ)

AF:

0.000159

AC:

AN:

25186

East Asian (EAS)

AF:

0.00123

AC:

AN:

38902

South Asian (SAS)

AF:

0.00440

AC:

364

AN:

82820

European-Finnish (FIN)

AF:

0.00551

AC:

291

AN:

52860

Middle Eastern (MID)

AF:

0.000975

AC:

AN:

5130

European-Non Finnish (NFE)

AF:

0.00772

AC:

7399

AN:

958556

Other (OTH)

AF:

0.00812

AC:

447

AN:

55038

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

461

923

1384

1846

2307

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

290

580

870

1160

1450

<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:

0.00764

AC:

1163

AN:

152250

Hom.:

Cov.:

AF XY:

0.00764

AC XY:

569

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.00378

AC:

157

AN:

41570

American (AMR)

AF:

0.0243

AC:

372

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000773

AC:

AN:

5176

South Asian (SAS)

AF:

0.00435

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00481

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00737

AC:

501

AN:

68006

Other (OTH)

AF:

0.00664

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

117

176

234

293

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00731

Hom.:

Bravo

AF:

0.00929

TwinsUK

AF:

0.00701

AC:

ALSPAC

AF:

0.00649

AC:

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.00767

AC:

ExAC

AF:

0.00964

AC:

1170

Asia WGS

AF:

0.00462

AC:

AN:

3478

EpiCase

AF:

0.00720

EpiControl

AF:

0.00610

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Asphyxiating thoracic dystrophy 2 (2)

not provided (2)

not specified (2)

Connective tissue disorder (1)

Jeune thoracic dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

0.090

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.59

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.96

MetaRNN

Benign

0.0087

MetaSVM

Uncertain

-0.029

MutationAssessor

Pathogenic

3.0

PhyloP100

4.5

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-5.0

REVEL

Uncertain

0.45

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.73

MPC

0.65

ClinPred

0.040

GERP RS

5.1

PromoterAI

-0.0072

Neutral

(source)

Varity_R

0.47

gMVP

0.68

Mutation Taster

=90/10

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.75

SpliceAI score (max)

0.010

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

Computational scores

Splicing

Publications

Other links and lift over