rs704793

Positions:

• chr2-27458798-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.2858G>A​(p.Arg953His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00135 in 1,614,136 control chromosomes in the GnomAD database, including 12 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.0055 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00092 (8 hom.)
• Consequence: IFT172 NM_015662.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.161

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=0.009088665).
• BP6: Variant 2-27458798-C-T is Benign according to our data. Variant chr2-27458798-C-T is described in ClinVar as [Benign]. Clinvar id is 380464.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00549 (836/152288) while in subpopulation AFR AF= 0.0177 (737/41554). AF 95% confidence interval is 0.0167. There are 4 homozygotes in gnomad4. There are 411 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IFT172	NM_015662.3	c.2858G>A	p.Arg953His	missense_variant	26/48	ENST00000260570.8	NP_056477.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IFT172	ENST00000260570.8	c.2858G>A	p.Arg953His	missense_variant	26/48	1	NM_015662.3	ENSP00000260570	P1

Frequencies

GnomAD3 genomes AF: 0.00548 AC: 834 AN: 152170 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0177

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000867

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00179 AC: 451 AN: 251378 Hom.: 1 AF XY: 0.00148 AC XY: 201 AN XY: 135850

Gnomad AFR exome AF: 0.0188

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.000647

Gnomad NFE exome AF: 0.000783

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000919 AC: 1344 AN: 1461848 Hom.: 8 Cov.: 31 AF XY: 0.000857 AC XY: 623 AN XY: 727222

Gnomad4 AFR exome AF: 0.0205

Gnomad4 AMR exome AF: 0.00112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.000374

Gnomad4 NFE exome AF: 0.000452

Gnomad4 OTH exome AF: 0.00108

GnomAD4 genome AF: 0.00549 AC: 836 AN: 152288 Hom.: 4 Cov.: 32 AF XY: 0.00552 AC XY: 411 AN XY: 74466

Gnomad4 AFR AF: 0.0177

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.000867

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00193 Hom.: 2

Bravo AF: 0.00588

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.0136 AC: 60

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00197 AC: 239

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000830

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 24, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jan 10, 2022

- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	15
DANN	Benign	0.92
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0091	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.54	N
MutationTaster	Benign	0.52	D
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.63	N
REVEL	Benign	0.046
Sift	Benign	0.25	T
Sift4G	Benign	0.20	T
Polyphen		0.0	B
Vest4		0.097
MVP		0.061
MPC		0.22
ClinPred		0.026	T
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.014
gMVP		0.28

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: rs704793; hg19: chr2-27681665;