rs9836202

chr3-129515606-C-T

Variant summary

Our verdict is Benign. Variant got -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. 2/2 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:4
• Conservation: PhyloP100: 0.361

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 343265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-129515606-C-T is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 32 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IFT122	NM_052989.3	c.3265+7C>T		splice_region_variant, intron_variant		ENST00000348417.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFT122	ENST00000348417.7	c.3265+7C>T		splice_region_variant, intron_variant		1	NM_052989.3

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

GnomAD3 exomes AF: 0.00363 AC: 901 AN: 248392 Hom.: 19 AF XY: 0.00311 AC XY: 417 AN XY: 134244

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 SAS exome AF: 0.0000660

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

Gnomad4 AFR exome AF: 0.0457

Gnomad4 AMR exome AF: 0.00404

Gnomad4 ASJ exome AF: 0.00164

Gnomad4 EAS exome AF: 0.0000259

Gnomad4 SAS exome AF: 0.000122

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000305

Gnomad4 OTH exome AF: 0.00468

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

Gnomad4 AFR AF: 0.0420

Gnomad4 AMR AF: 0.00909

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000471

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.00667 Hom.: 6

Bravo AF: 0.0151

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cranioectodermal dysplasia 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 16, 2019

- -

Connective tissue disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
Cadd	Benign	3.5
Dann	Benign	0.88

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

Publications

LitVar

Other links and lift over

dbSNP: rs9836202; hg19: chr3-129234449;