rs267607193

Variant names:

• chr3-129440351-G-C
• rs267607193
• NM_052989.3:c.21G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP5

The NM_052989.3(IFT122):​c.21G>C​(p.Trp7Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W7S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IFT122 NM_052989.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 6.07
• Publications: 2 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]

MBD4 (HGNC:6919): (methyl-CpG binding domain 4, DNA glycosylase) The protein encoded by this gene is a member of a family of nuclear proteins related by the presence of a methyl-CpG binding domain (MBD). These proteins are capable of binding specifically to methylated DNA, and some members can also repress transcription from methylated gene promoters. This protein contains an MBD domain at the N-terminus that functions both in binding to methylated DNA and in protein interactions and a C-terminal mismatch-specific glycosylase domain that is involved in DNA repair. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jan 2013]

MBD4 Gene-Disease associations (from GenCC):

• tumor predisposition syndrome 2

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
• melanoma, uveal, susceptibility to, 1

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-129440351-G-C is Pathogenic according to our data. Variant chr3-129440351-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 4638.Status of the report is no_assertion_criteria_provided, 0 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.21G>C	p.Trp7Cys	missense	Exon 1 of 30	NP_443715.1	Q9HBG6-1
	IFT122	NM_052985.4		c.21G>C	p.Trp7Cys	missense	Exon 1 of 31	NP_443711.2	Q9HBG6-5
	IFT122	NM_001410808.1		c.21G>C	p.Trp7Cys	missense	Exon 1 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.21G>C	p.Trp7Cys	missense	Exon 1 of 30	ENSP00000324005.4	Q9HBG6-1
	IFT122	ENST00000296266.7	TSL:1	c.21G>C	p.Trp7Cys	missense	Exon 1 of 31	ENSP00000296266.3	Q9HBG6-5
	IFT122	ENST00000507564.5	TSL:1	c.21G>C	p.Trp7Cys	missense	Exon 1 of 30	ENSP00000425536.1	Q9HBG6-6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Cranioectodermal dysplasia 1 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.82	D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.079	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Uncertain	0.0087	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		6.1
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-9.1	D
REVEL	Uncertain	0.47
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.63
MutPred		0.61		Loss of catalytic residue at L5 (P = 0.004)
MVP		0.90
MPC		1.0
ClinPred		1.0	D
GERP RS		5.9
PromoterAI		-0.050	Neutral
Varity_R		0.94
gMVP		0.77
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs267607193; hg19: chr3-129159194;