chr3-129514530-C-T

Variant names:

• chr3-129514530-C-T
• rs76881473
• NM_052989.3:c.3129C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_052989.3(IFT122):​c.3129C>T​(p.Arg1043Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00335 in 1,614,226 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0035 (15 hom.)
• Consequence: IFT122 NM_052989.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -0.00900
• 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]

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.27).
• BP6: Variant 3-129514530-C-T is Benign according to our data. Variant chr3-129514530-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 195991.
• BP7: Synonymous conserved (PhyloP=-0.009 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00204 (311/152360) while in subpopulation NFE AF = 0.00372 (253/68040). AF 95% confidence interval is 0.00334. There are 0 homozygotes in GnomAd4. There are 135 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 15 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.3129C>T	p.Arg1043Arg	synonymous	Exon 25 of 30	NP_443715.1
	IFT122	NM_052985.4		c.3282C>T	p.Arg1094Arg	synonymous	Exon 26 of 31	NP_443711.2
	IFT122	NM_001410808.1		c.3132C>T	p.Arg1044Arg	synonymous	Exon 25 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.3129C>T	p.Arg1043Arg	synonymous	Exon 25 of 30	ENSP00000324005.4
	IFT122	ENST00000296266.7	TSL:1	c.3282C>T	p.Arg1094Arg	synonymous	Exon 26 of 31	ENSP00000296266.3
	IFT122	ENST00000507564.5	TSL:1	c.3108C>T	p.Arg1036Arg	synonymous	Exon 25 of 30	ENSP00000425536.1

Frequencies

GnomAD3 genomes AF: 0.00204 AC: 311 AN: 152242 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00372

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00251 AC: 631 AN: 251248 AF XY: 0.00247

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00286

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000832

Gnomad NFE exome AF: 0.00393

Gnomad OTH exome AF: 0.00392

GnomAD4 exome AF: 0.00349 AC: 5104 AN: 1461866 Hom.: 15 Cov.: 31 AF XY: 0.00349 AC XY: 2538 AN XY: 727238

African (AFR) AF: 0.000508 AC: 17 AN: 33480

American (AMR) AF: 0.00286 AC: 128 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00148 AC: 128 AN: 86258

European-Finnish (FIN) AF: 0.00101 AC: 54 AN: 53406

Middle Eastern (MID) AF: 0.00433 AC: 25 AN: 5768

European-Non Finnish (NFE) AF: 0.00414 AC: 4600 AN: 1112002

Other (OTH) AF: 0.00245 AC: 148 AN: 60396

GnomAD4 genome AF: 0.00204 AC: 311 AN: 152360 Hom.: 0 Cov.: 33 AF XY: 0.00181 AC XY: 135 AN XY: 74504

African (AFR) AF: 0.000457 AC: 19 AN: 41584

American (AMR) AF: 0.00105 AC: 16 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4828

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00372 AC: 253 AN: 68040

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00289 Hom.: 1

Bravo AF: 0.00209

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00431

EpiControl AF: 0.00421

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	4.1
DANN	Benign	0.59
PhyloP100		-0.0090
Mutation Taster		=100/0	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: rs76881473; hg19: chr3-129233373; COSMIC: COSV106419451;