rs61747073

Positions:

• chr2-27459442-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015662.3(IFT172):​c.2723G>A​(p.Arg908Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0173 in 1,614,152 control chromosomes in the GnomAD database, including 276 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R908W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.012 (12 hom., cov: 32)
  • Exomes 𝑓: 0.018 (264 hom.)
• Consequence: IFT172 NM_015662.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.190

Genes affected

IFT172 (HGNC:30391): (intraflagellar transport 172) This gene encodes a subunit of the intraflagellar transport subcomplex IFT-B. Subcomplexes IFT-A and IFT-B are necessary for ciliary assembly and maintenance. Mutations in this gene have been associated with skeletal ciliopathies, with or without polydactyly, such as such short-rib thoracic dysplasias 1, 9 or 10. [provided by RefSeq, Mar 2014]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002185136).
• BP6: Variant 2-27459442-C-T is Benign according to our data. Variant chr2-27459442-C-T is described in ClinVar as [Benign]. Clinvar id is 379641.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-27459442-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0122 (1861/152278) while in subpopulation NFE AF= 0.0183 (1245/68030). AF 95% confidence interval is 0.0175. There are 12 homozygotes in gnomad4. There are 866 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IFT172	NM_015662.3	c.2723G>A	p.Arg908Gln	missense_variant	25/48	ENST00000260570.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFT172	ENST00000260570.8	c.2723G>A	p.Arg908Gln	missense_variant	25/48	1	NM_015662.3	P1

Frequencies

GnomAD3 genomes AF: 0.0122 AC: 1861 AN: 152160 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.00323

Gnomad AMI AF: 0.0625

Gnomad AMR AF: 0.00589

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00581

Gnomad FIN AF: 0.0266

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0183

Gnomad OTH AF: 0.00718

GnomAD3 exomes AF: 0.0130 AC: 3264 AN: 251430 Hom.: 23 AF XY: 0.0134 AC XY: 1818 AN XY: 135884

Gnomad AFR exome AF: 0.00418

Gnomad AMR exome AF: 0.00445

Gnomad ASJ exome AF: 0.00179

Gnomad EAS exome AF: 0.000217

Gnomad SAS exome AF: 0.00777

Gnomad FIN exome AF: 0.0233

Gnomad NFE exome AF: 0.0195

Gnomad OTH exome AF: 0.0103

GnomAD4 exome AF: 0.0179 AC: 26104 AN: 1461874 Hom.: 264 Cov.: 31 AF XY: 0.0175 AC XY: 12749 AN XY: 727242

Gnomad4 AFR exome AF: 0.00245

Gnomad4 AMR exome AF: 0.00494

Gnomad4 ASJ exome AF: 0.00245

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.00763

Gnomad4 FIN exome AF: 0.0240

Gnomad4 NFE exome AF: 0.0206

Gnomad4 OTH exome AF: 0.0140

GnomAD4 genome AF: 0.0122 AC: 1861 AN: 152278 Hom.: 12 Cov.: 32 AF XY: 0.0116 AC XY: 866 AN XY: 74456

Gnomad4 AFR AF: 0.00322

Gnomad4 AMR AF: 0.00589

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00581

Gnomad4 FIN AF: 0.0266

Gnomad4 NFE AF: 0.0183

Gnomad4 OTH AF: 0.00711

Alfa AF: 0.0159 Hom.: 27

Bravo AF: 0.0111

TwinsUK AF: 0.0229 AC: 85

ALSPAC AF: 0.0163 AC: 63

ESP6500AA AF: 0.00522 AC: 23

ESP6500EA AF: 0.0158 AC: 136

ExAC AF: 0.0133 AC: 1614

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.0158

EpiControl AF: 0.0167

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 08, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Short-rib thoracic dysplasia 10 with or without polydactyly;C4225342:Retinitis pigmentosa 71 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Retinal dystrophy Benign:1

Benign, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	15
DANN	Uncertain	0.97
DEOGEN2	Benign	0.069	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.081	N
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.2	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	0.90	N
REVEL	Benign	0.079
Sift	Benign	0.56	T
Sift4G	Benign	0.61	T
Polyphen		0.0020	B
Vest4		0.10
MPC		0.21
ClinPred		0.0073	T
GERP RS		0.40
Varity_R		0.015
gMVP		0.13

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

Publications

LitVar

Other links and lift over

dbSNP: rs61747073; hg19: chr2-27682309; COSMIC: COSV53140420; COSMIC: COSV53140420;