rs61744639

Variant names:

• chr3-129478141-C-T
• rs61744639
• NM_052989.3:c.1273C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_052989.3(IFT122):​c.1273C>T​(p.Arg425Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00473 in 1,614,106 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R425L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0045 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0048 (41 hom.)
• Consequence: IFT122 NM_052989.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 4.70
• Publications: 11 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 (MetaRNN=0.009804696).
• BP6: Variant 3-129478141-C-T is Benign according to our data. Variant chr3-129478141-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 288335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00446 (679/152272) while in subpopulation NFE AF = 0.00703 (478/68026). AF 95% confidence interval is 0.00651. There are 4 homozygotes in GnomAd4. There are 315 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

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.1273C>T	p.Arg425Trp	missense	Exon 12 of 30	NP_443715.1	Q9HBG6-1
	IFT122	NM_052985.4		c.1426C>T	p.Arg476Trp	missense	Exon 13 of 31	NP_443711.2	Q9HBG6-5
	IFT122	NM_001410808.1		c.1273C>T	p.Arg425Trp	missense	Exon 12 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.1273C>T	p.Arg425Trp	missense	Exon 12 of 30	ENSP00000324005.4	Q9HBG6-1
	IFT122	ENST00000296266.7	TSL:1	c.1426C>T	p.Arg476Trp	missense	Exon 13 of 31	ENSP00000296266.3	Q9HBG6-5
	IFT122	ENST00000507564.5	TSL:1	c.1249C>T	p.Arg417Trp	missense	Exon 12 of 30	ENSP00000425536.1	Q9HBG6-6

Frequencies

GnomAD3 genomes AF: 0.00447 AC: 680 AN: 152154 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.0343

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00302

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00703

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00517 AC: 1300 AN: 251436 AF XY: 0.00539

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000896

Gnomad ASJ exome AF: 0.0333

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00388

Gnomad NFE exome AF: 0.00586

Gnomad OTH exome AF: 0.00538

GnomAD4 exome AF: 0.00476 AC: 6953 AN: 1461834 Hom.: 41 Cov.: 32 AF XY: 0.00501 AC XY: 3646 AN XY: 727224

African (AFR) AF: 0.000388 AC: 13 AN: 33480

American (AMR) AF: 0.000894 AC: 40 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0319 AC: 834 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00392 AC: 338 AN: 86256

European-Finnish (FIN) AF: 0.00389 AC: 208 AN: 53420

Middle Eastern (MID) AF: 0.00347 AC: 20 AN: 5768

European-Non Finnish (NFE) AF: 0.00468 AC: 5207 AN: 1111960

Other (OTH) AF: 0.00485 AC: 293 AN: 60390

GnomAD4 genome AF: 0.00446 AC: 679 AN: 152272 Hom.: 4 Cov.: 32 AF XY: 0.00423 AC XY: 315 AN XY: 74456

African (AFR) AF: 0.000409 AC: 17 AN: 41546

American (AMR) AF: 0.000654 AC: 10 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0343 AC: 119 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4826

European-Finnish (FIN) AF: 0.00302 AC: 32 AN: 10604

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.00703 AC: 478 AN: 68026

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00635 Hom.: 23

Bravo AF: 0.00365

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00651 AC: 56

ExAC AF: 0.00475 AC: 577

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00594

EpiControl AF: 0.00492

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	2	not specified (2)
-	-	1	Connective tissue disorder (1)
-	-	1	Cranioectodermal dysplasia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.72	D
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.29	D
MetaRNN	Benign	0.0098	T
MetaSVM	Uncertain	0.49	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		4.7
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-6.0	D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.52
MVP		0.95
MPC		0.78
ClinPred		0.024	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.49
gMVP		0.60
Mutation Taster		=99/1	polymorphism

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: rs61744639; hg19: chr3-129196984;