Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4BP6BP7BS1BS2

The NM_052989.3(IFT122):c.1026C>T(p.Asp342Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000756 in 1,614,210 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00080 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00075 ( 3 hom. )

Consequence

IFT122
NM_052989.3 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 1.00

Publications

1 publications found

Variant links:

Genes affected

IFT122 (HGNC:13556): (intraflagellar transport 122) This gene encodes a member of the WD repeat protein family. WD repeats are minimally conserved regions of approximately 40 amino acids typically bracketed by gly-his and trp-asp (GH-WD), which may facilitate formation of heterotrimeric or multiprotein complexes. Members of this family are involved in a variety of cellular processes, including cell cycle progression, signal transduction, apoptosis, and gene regulation. This cytoplasmic protein contains seven WD repeats and an AF-2 domain which function by recruiting coregulatory molecules and in transcriptional activation. Mutations in this gene cause cranioectodermal dysplasia-1. A related pseudogene is located on chromosome 3. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2013]

IFT122 Gene-Disease associations (from GenCC):

cranioectodermal dysplasia 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, ClinGen, Labcorp Genetics (formerly Invitae)
cranioectodermal dysplasia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

IFT122 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.264).

BP6

Variant 3-129476680-C-T is Benign according to our data. Variant chr3-129476680-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 262266.

BP7

Synonymous conserved (PhyloP=1 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000801 (122/152318) while in subpopulation EAS AF = 0.00444 (23/5178). AF 95% confidence interval is 0.00304. There are 1 homozygotes in GnomAd4. There are 58 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_052989.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
IFT122	NM_052989.3	MANE Select	c.1026C>T	p.Asp342Asp	synonymous	Exon 11 of 30	NP_443715.1
IFT122	NM_052985.4		c.1179C>T	p.Asp393Asp	synonymous	Exon 12 of 31	NP_443711.2
IFT122	NM_001410808.1		c.1026C>T	p.Asp342Asp	synonymous	Exon 11 of 30	NP_001397737.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
IFT122	ENST00000348417.7	TSL:1 MANE Select	c.1026C>T	p.Asp342Asp	synonymous	Exon 11 of 30	ENSP00000324005.4
IFT122	ENST00000296266.7	TSL:1	c.1179C>T	p.Asp393Asp	synonymous	Exon 12 of 31	ENSP00000296266.3
IFT122	ENST00000507564.5	TSL:1	c.1002C>T	p.Asp334Asp	synonymous	Exon 11 of 30	ENSP00000425536.1

Frequencies

GnomAD3 genomes

AF:

0.000802

AC:

122

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.00443

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000955

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.000863

AC:

217

AN:

251432

AF XY:

0.000876

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00377

Gnomad EAS exome

AF:

0.00283

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.000941

Gnomad OTH exome

AF:

0.000814

GnomAD4 exome

AF:

0.000751

AC:

1098

AN:

1461892

Hom.:

Cov.:

AF XY:

0.000751

AC XY:

546

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.000209

AC:

AN:

33480

American (AMR)

AF:

0.0000671

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00367

AC:

AN:

26136

East Asian (EAS)

AF:

0.00836

AC:

332

AN:

39700

South Asian (SAS)

AF:

0.0000812

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000262

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000522

AC:

580

AN:

1112010

Other (OTH)

AF:

0.000977

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

139

208

278

347

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.000801

AC:

122

AN:

152318

Hom.:

Cov.:

AF XY:

0.000779

AC XY:

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.000265

AC:

AN:

41568

American (AMR)

AF:

0.0000654

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00461

AC:

AN:

3472

East Asian (EAS)

AF:

0.00444

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000283

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000955

AC:

AN:

68040

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

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:

0.000969

Hom.:

Bravo

AF:

0.000680

EpiCase

AF:

0.000600

EpiControl

AF:

0.000415

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cranioectodermal dysplasia 1 (2)

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.39

CADD

Benign

7.3

(source)

DANN

Benign

0.66

PhyloP100

1.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs79187669

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over