rs61740161

Variant names:

• chr3-129495459-G-A
• rs61740161
• NM_052989.3:c.2060G>A

Your query was ambiguous. Multiple possible variants found:

• chr3-129495459-G-A
• chr3-129495459-G-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.2060G>A​(p.Arg687Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0839 in 1,613,696 control chromosomes in the GnomAD database, including 5,995 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict 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. R687W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.077 (504 hom., cov: 32)
  • Exomes 𝑓: 0.085 (5491 hom.)
• Consequence: IFT122 NM_052989.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.81
• Publications: 10 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: PanelApp Australia, G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• 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=0.0018106997).
• BP6: Variant 3-129495459-G-A is Benign according to our data. Variant chr3-129495459-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262270.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0968 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.2060G>A	p.Arg687Gln	missense	Exon 18 of 30	NP_443715.1
	IFT122	NM_052985.4		c.2213G>A	p.Arg738Gln	missense	Exon 19 of 31	NP_443711.2
	IFT122	NM_001410808.1		c.2060G>A	p.Arg687Gln	missense	Exon 18 of 30	NP_001397737.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFT122	ENST00000348417.7	TSL:1 MANE Select	c.2060G>A	p.Arg687Gln	missense	Exon 18 of 30	ENSP00000324005.4
	IFT122	ENST00000296266.7	TSL:1	c.2213G>A	p.Arg738Gln	missense	Exon 19 of 31	ENSP00000296266.3
	IFT122	ENST00000507564.5	TSL:1	c.2036G>A	p.Arg679Gln	missense	Exon 18 of 30	ENSP00000425536.1

Frequencies

GnomAD3 genomes AF: 0.0766 AC: 11645 AN: 152086 Hom.: 503 Cov.: 32

Gnomad AFR AF: 0.0667

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0770

Gnomad ASJ AF: 0.161

Gnomad EAS AF: 0.0620

Gnomad SAS AF: 0.104

Gnomad FIN AF: 0.0381

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0833

Gnomad OTH AF: 0.0951

GnomAD2 exomes AF: 0.0769 AC: 19306 AN: 251098 AF XY: 0.0805

Gnomad AFR exome AF: 0.0658

Gnomad AMR exome AF: 0.0548

Gnomad ASJ exome AF: 0.151

Gnomad EAS exome AF: 0.0602

Gnomad FIN exome AF: 0.0354

Gnomad NFE exome AF: 0.0806

Gnomad OTH exome AF: 0.0933

GnomAD4 exome AF: 0.0846 AC: 123666 AN: 1461492 Hom.: 5491 Cov.: 32 AF XY: 0.0864 AC XY: 62815 AN XY: 727042

African (AFR) AF: 0.0670 AC: 2243 AN: 33472

American (AMR) AF: 0.0585 AC: 2614 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.163 AC: 4256 AN: 26132

East Asian (EAS) AF: 0.0491 AC: 1951 AN: 39696

South Asian (SAS) AF: 0.114 AC: 9847 AN: 86232

European-Finnish (FIN) AF: 0.0382 AC: 2041 AN: 53406

Middle Eastern (MID) AF: 0.128 AC: 737 AN: 5766

European-Non Finnish (NFE) AF: 0.0849 AC: 94434 AN: 1111712

Other (OTH) AF: 0.0918 AC: 5543 AN: 60366

GnomAD4 genome AF: 0.0766 AC: 11654 AN: 152204 Hom.: 504 Cov.: 32 AF XY: 0.0759 AC XY: 5646 AN XY: 74404

African (AFR) AF: 0.0667 AC: 2771 AN: 41534

American (AMR) AF: 0.0769 AC: 1175 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.161 AC: 558 AN: 3470

East Asian (EAS) AF: 0.0616 AC: 319 AN: 5178

South Asian (SAS) AF: 0.104 AC: 503 AN: 4822

European-Finnish (FIN) AF: 0.0381 AC: 404 AN: 10604

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.0833 AC: 5667 AN: 68002

Other (OTH) AF: 0.0965 AC: 204 AN: 2114

Alfa AF: 0.0802 Hom.: 110

Bravo AF: 0.0790

TwinsUK AF: 0.0723 AC: 268

ALSPAC AF: 0.0765 AC: 295

ESP6500AA AF: 0.0651 AC: 287

ESP6500EA AF: 0.0856 AC: 736

ExAC AF: 0.0773 AC: 9390

Asia WGS AF: 0.0980 AC: 343 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Cranioectodermal dysplasia 1 (2)
-	-	2	not provided (2)
-	-	1	Cranioectodermal dysplasia (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.071
Eigen_PC	Benign	0.046
FATHMM_MKL	Benign	0.64	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.8
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.18
Sift	Benign	0.21	T
Sift4G	Benign	0.25	T
Polyphen		0.020	B
Vest4		0.26
MPC		0.26
ClinPred		0.013	T
GERP RS		3.4
Varity_R		0.054
gMVP		0.33
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs61740161; hg19: chr3-129214302; COSMIC: COSV56199942;