3-129492134-G-C

Variant names:

• chr3-129492134-G-C
• rs2285354
• NM_052989.3:c.1993-7G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_052989.3(IFT122):​c.1993-7G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.22 in 1,604,430 control chromosomes in the GnomAD database, including 63,735 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (17995 hom., cov: 32)
  • Exomes 𝑓: 0.20 (45740 hom.)
• Consequence: IFT122 NM_052989.3 splice_region, intron
• Scores: Splicing: ADA: 0.00002742
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.306
• Publications: 15 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=-0.82).
• BP6: Variant 3-129492134-G-C is Benign according to our data. Variant chr3-129492134-G-C is described in ClinVar as Benign. ClinVar VariationId is 194901.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.82 is higher than 0.05.

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.1993-7G>C		splice_region intron	N/A	NP_443715.1	Q9HBG6-1
	IFT122	NM_052985.4		c.2146-7G>C		splice_region intron	N/A	NP_443711.2	Q9HBG6-5
	IFT122	NM_001410808.1		c.1993-7G>C		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.1993-7G>C		splice_region intron	N/A	ENSP00000324005.4	Q9HBG6-1
	IFT122	ENST00000296266.7	TSL:1	c.2146-7G>C		splice_region intron	N/A	ENSP00000296266.3	Q9HBG6-5
	IFT122	ENST00000507564.5	TSL:1	c.1969-7G>C		splice_region intron	N/A	ENSP00000425536.1	Q9HBG6-6

Frequencies

GnomAD3 genomes AF: 0.382 AC: 58054 AN: 151928 Hom.: 17931 Cov.: 32

Gnomad AFR AF: 0.827

Gnomad AMI AF: 0.179

Gnomad AMR AF: 0.345

Gnomad ASJ AF: 0.288

Gnomad EAS AF: 0.673

Gnomad SAS AF: 0.380

Gnomad FIN AF: 0.0745

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.155

Gnomad OTH AF: 0.348

GnomAD2 exomes AF: 0.282 AC: 70818 AN: 251436 AF XY: 0.272

Gnomad AFR exome AF: 0.841

Gnomad AMR exome AF: 0.279

Gnomad ASJ exome AF: 0.279

Gnomad EAS exome AF: 0.676

Gnomad FIN exome AF: 0.0704

Gnomad NFE exome AF: 0.157

Gnomad OTH exome AF: 0.246

GnomAD4 exome AF: 0.203 AC: 295254 AN: 1452384 Hom.: 45740 Cov.: 30 AF XY: 0.207 AC XY: 149729 AN XY: 723160

African (AFR) AF: 0.854 AC: 28231 AN: 33062

American (AMR) AF: 0.282 AC: 12591 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.281 AC: 7321 AN: 26036

East Asian (EAS) AF: 0.661 AC: 26150 AN: 39574

South Asian (SAS) AF: 0.372 AC: 31988 AN: 85960

European-Finnish (FIN) AF: 0.0743 AC: 3965 AN: 53380

Middle Eastern (MID) AF: 0.299 AC: 1713 AN: 5736

European-Non Finnish (NFE) AF: 0.152 AC: 167935 AN: 1103950

Other (OTH) AF: 0.256 AC: 15360 AN: 59970

GnomAD4 genome AF: 0.383 AC: 58183 AN: 152046 Hom.: 17995 Cov.: 32 AF XY: 0.383 AC XY: 28431 AN XY: 74290

African (AFR) AF: 0.827 AC: 34348 AN: 41518

American (AMR) AF: 0.345 AC: 5269 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.288 AC: 998 AN: 3470

East Asian (EAS) AF: 0.672 AC: 3462 AN: 5148

South Asian (SAS) AF: 0.380 AC: 1831 AN: 4820

European-Finnish (FIN) AF: 0.0745 AC: 786 AN: 10554

Middle Eastern (MID) AF: 0.265 AC: 78 AN: 294

European-Non Finnish (NFE) AF: 0.155 AC: 10512 AN: 67966

Other (OTH) AF: 0.349 AC: 736 AN: 2110

Alfa AF: 0.161 Hom.: 827

Bravo AF: 0.420

EpiCase AF: 0.173

EpiControl AF: 0.179

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Cranioectodermal dysplasia 1 (3)
-	-	1	Cranioectodermal dysplasia (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.7
DANN	Benign	0.57
PhyloP100		0.31
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000027
dbscSNV1_RF	Benign	0.010
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: rs2285354; hg19: chr3-129210977; COSMIC: COSV56200944; COSMIC: COSV56200944;