3-129483546-G-T

Variant names:

• chr3-129483546-G-T
• rs786205566
• NM_052989.3:c.1715G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_052989.3(IFT122):​c.1715G>T​(p.Gly572Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: IFT122 NM_052989.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.43
• Publications: 4 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

ENSG00000299667 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.868
• PP5: Variant 3-129483546-G-T is Pathogenic according to our data. Variant chr3-129483546-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 191184.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1715G>T	p.Gly572Val	missense	Exon 15 of 30	NP_443715.1	Q9HBG6-1
	IFT122	NM_052985.4		c.1868G>T	p.Gly623Val	missense	Exon 16 of 31	NP_443711.2	Q9HBG6-5
	IFT122	NM_001410808.1		c.1715G>T	p.Gly572Val	missense	Exon 15 of 30	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.1715G>T	p.Gly572Val	missense	Exon 15 of 30	ENSP00000324005.4	Q9HBG6-1
	IFT122	ENST00000296266.7	TSL:1	c.1868G>T	p.Gly623Val	missense	Exon 16 of 31	ENSP00000296266.3	Q9HBG6-5
	IFT122	ENST00000507564.5	TSL:1	c.1691G>T	p.Gly564Val	missense	Exon 15 of 30	ENSP00000425536.1	Q9HBG6-6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D
Eigen	Pathogenic	0.68
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		9.4
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-7.1	D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.96	D
Vest4		0.92
MutPred		0.56		Loss of sheet (P = 0.0457)
MVP		0.74
MPC		0.63
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.73
gMVP		0.77
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.21		Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs786205566; hg19: chr3-129202389;