Genetic Variant IFT81:p.Asn22Thr (chr12-110127445-A-C) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_014055.4(IFT81):c.65A>C(p.Asn22Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00262 in 1,608,994 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N22D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0015 ( 1 hom., cov: 31)

Exomes 𝑓: 0.0027 ( 5 hom. )

Consequence

IFT81
NM_014055.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: 8.95

Publications

6 publications found

Variant links:

Genes affected

IFT81 (HGNC:14313): (intraflagellar transport 81) The protein encoded by this gene, together with IFT74, forms a tubulin-binding module of intraflagellar transport complex B. This module is involved in transport of tubulin within the cilium, and the encoded protein is required for ciliogenesis. Mutations in this gene are a cause of short-rib polydactyly syndromes. [provided by RefSeq, Dec 2016]

IFT81 Gene-Disease associations (from GenCC):

short-rib thoracic dysplasia 19 with or without polydactyly
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
ciliopathy
Inheritance: AR Classification: LIMITED Submitted by: Franklin by Genoox

IFT81 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.022544831).

BP6

Variant 12-110127445-A-C is Benign according to our data. Variant chr12-110127445-A-C is described in ClinVar as Likely_benign. ClinVar VariationId is 731781.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00153 (233/152312) while in subpopulation NFE AF = 0.00281 (191/68032). AF 95% confidence interval is 0.00248. There are 1 homozygotes in GnomAd4. There are 93 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014055.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IFT81	NM_014055.4	MANE Select	c.65A>C	p.Asn22Thr	missense	Exon 2 of 19	NP_054774.2
IFT81	NM_001143779.2		c.65A>C	p.Asn22Thr	missense	Exon 2 of 19	NP_001137251.1	Q8WYA0-1
IFT81	NM_001347946.2		c.65A>C	p.Asn22Thr	missense	Exon 2 of 12	NP_001334875.1	Q8WYA0-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IFT81	ENST00000242591.10	TSL:1 MANE Select	c.65A>C	p.Asn22Thr	missense	Exon 2 of 19	ENSP00000242591.5	Q8WYA0-1
IFT81	ENST00000552912.5	TSL:1	c.65A>C	p.Asn22Thr	missense	Exon 2 of 19	ENSP00000449718.1	Q8WYA0-1
IFT81	ENST00000361948.8	TSL:1	c.65A>C	p.Asn22Thr	missense	Exon 2 of 12	ENSP00000355372.4	Q8WYA0-3

Frequencies

GnomAD3 genomes

AF:

0.00153

AC:

233

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000458

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00281

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00130

AC:

317

AN:

243004

AF XY:

0.00133

show subpopulations

Gnomad AFR exome

AF:

0.000468

Gnomad AMR exome

AF:

0.000836

Gnomad ASJ exome

AF:

0.000104

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000934

Gnomad NFE exome

AF:

0.00238

Gnomad OTH exome

AF:

0.00184

GnomAD4 exome

AF:

0.00274

AC:

3990

AN:

1456682

Hom.:

Cov.:

AF XY:

0.00263

AC XY:

1908

AN XY:

724374

show subpopulations

African (AFR)

AF:

0.000300

AC:

AN:

33332

American (AMR)

AF:

0.000865

AC:

AN:

43914

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25744

East Asian (EAS)

AF:

0.00

AC:

AN:

39558

South Asian (SAS)

AF:

0.000129

AC:

AN:

85278

European-Finnish (FIN)

AF:

0.0000939

AC:

AN:

53222

Middle Eastern (MID)

AF:

0.000521

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00340

AC:

3777

AN:

1109692

Other (OTH)

AF:

0.00243

AC:

146

AN:

60182

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

206

411

617

822

1028

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

156

312

468

624

780

<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:

0.00153

AC:

233

AN:

152312

Hom.:

Cov.:

AF XY:

0.00125

AC XY:

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.000457

AC:

AN:

41576

American (AMR)

AF:

0.00124

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00281

AC:

191

AN:

68032

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00233

Hom.:

Bravo

AF:

0.00171

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00291

AC:

ExAC

AF:

0.00125

AC:

152

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

IFT81-related disorder (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.11

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.039

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.052

MetaRNN

Benign

0.023

MetaSVM

Uncertain

-0.16

MutationAssessor

Benign

1.8

PhyloP100

8.9

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-2.4

REVEL

Uncertain

0.36

Sift

Benign

0.30

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.80

MVP

0.86

MPC

0.31

ClinPred

0.057

GERP RS

6.1

Varity_R

0.26

gMVP

0.52

Mutation Taster

=87/13

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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