rs9836202

Variant names:

• chr3-129515606-C-T
• rs9836202
• NM_052989.3:c.3265+7C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_052989.3(IFT122):​c.3265+7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00282 in 1,442,200 control chromosomes in the GnomAD database, including 76 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (33 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (43 hom.)
• Consequence: IFT122 NM_052989.3 splice_region, intron
• Scores: Splicing: ADA: 0.00007155
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.361
• Publications: 1 publications found

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: G2P, Labcorp Genetics (formerly Invitae), ClinGen
• cranioectodermal dysplasia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 3-129515606-C-T is Benign according to our data. Variant chr3-129515606-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 343265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0128 (1955/152304) while in subpopulation AFR AF = 0.042 (1747/41552). AF 95% confidence interval is 0.0404. There are 33 homozygotes in GnomAd4. There are 922 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 33 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFT122	NM_052989.3	MANE Select	c.3265+7C>T		splice_region intron	N/A	NP_443715.1	Q9HBG6-1
	IFT122	NM_052985.4		c.3418+7C>T		splice_region intron	N/A	NP_443711.2	Q9HBG6-5
	IFT122	NM_001410808.1		c.3268+7C>T		splice_region intron	N/A	NP_001397737.1	A0A8I5KSG5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFT122	ENST00000348417.7	TSL:1 MANE Select	c.3265+7C>T		splice_region intron	N/A	ENSP00000324005.4	Q9HBG6-1
	IFT122	ENST00000296266.7	TSL:1	c.3418+7C>T		splice_region intron	N/A	ENSP00000296266.3	Q9HBG6-5
	IFT122	ENST00000507564.5	TSL:1	c.3244+7C>T		splice_region intron	N/A	ENSP00000425536.1	Q9HBG6-6

Frequencies

GnomAD3 genomes AF: 0.0128 AC: 1942 AN: 152186 Hom.: 32 Cov.: 32

Gnomad AFR AF: 0.0418

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00916

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.0129

GnomAD2 exomes AF: 0.00363 AC: 901 AN: 248392 AF XY: 0.00311

Gnomad AFR exome AF: 0.0445

Gnomad AMR exome AF: 0.00320

Gnomad ASJ exome AF: 0.00150

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000481

Gnomad OTH exome AF: 0.00264

GnomAD4 exome AF: 0.00164 AC: 2117 AN: 1289896 Hom.: 43 Cov.: 20 AF XY: 0.00146 AC XY: 949 AN XY: 650074

African (AFR) AF: 0.0457 AC: 1314 AN: 28758

American (AMR) AF: 0.00404 AC: 179 AN: 44330

Ashkenazi Jewish (ASJ) AF: 0.00164 AC: 41 AN: 25024

East Asian (EAS) AF: 0.0000259 AC: 1 AN: 38610

South Asian (SAS) AF: 0.000122 AC: 10 AN: 82142

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53292

Middle Eastern (MID) AF: 0.00458 AC: 24 AN: 5242

European-Non Finnish (NFE) AF: 0.000305 AC: 292 AN: 957846

Other (OTH) AF: 0.00468 AC: 256 AN: 54652

GnomAD4 genome AF: 0.0128 AC: 1955 AN: 152304 Hom.: 33 Cov.: 32 AF XY: 0.0124 AC XY: 922 AN XY: 74482

African (AFR) AF: 0.0420 AC: 1747 AN: 41552

American (AMR) AF: 0.00909 AC: 139 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000471 AC: 32 AN: 68010

Other (OTH) AF: 0.0128 AC: 27 AN: 2114

Alfa AF: 0.00535 Hom.: 7

Bravo AF: 0.0151

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Cranioectodermal dysplasia 1 (2)
-	-	2	not provided (2)
-	-	1	Connective tissue disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	3.5
DANN	Benign	0.88
PhyloP100		0.36
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000072
dbscSNV1_RF	Benign	0.040
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

Other links and lift over

dbSNP: rs9836202; hg19: chr3-129234449;