rs79187669

chr3-129476680-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS1

The NM_052989.3(IFT122):c.1026C>T(p.Asp342=) 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 1.00

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• 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 id is 262266.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=3}. Variant chr3-129476680-C-T is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IFT122	NM_052989.3	c.1026C>T	p.Asp342=	synonymous_variant	11/30	ENST00000348417.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFT122	ENST00000348417.7	c.1026C>T	p.Asp342=	synonymous_variant	11/30	1	NM_052989.3

Frequencies

GnomAD3 genomes AF: 0.000802 AC: 122 AN: 152200 Hom.: 1 Cov.: 32

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

GnomAD3 exomes AF: 0.000863 AC: 217 AN: 251432 Hom.: 1 AF XY: 0.000876 AC XY: 119 AN XY: 135880

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 SAS exome AF: 0.000131

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.: 3 Cov.: 32 AF XY: 0.000751 AC XY: 546 AN XY: 727248

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00367

Gnomad4 EAS exome AF: 0.00836

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.000262

Gnomad4 NFE exome AF: 0.000522

Gnomad4 OTH exome AF: 0.000977

GnomAD4 genome AF: 0.000801 AC: 122 AN: 152318 Hom.: 1 Cov.: 32 AF XY: 0.000779 AC XY: 58 AN XY: 74466

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00444

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.000955

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000941 Hom.: 0

Bravo AF: 0.000680

EpiCase AF: 0.000600

EpiControl AF: 0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cranioectodermal dysplasia 1 Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 20, 2024	- -
Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 03, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 06, 2015	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
Cadd	Benign	7.3
Dann	Benign	0.66
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

LitVar

Other links and lift over

dbSNP: rs79187669; hg19: chr3-129195523;