rs61742074

chr2-27446270-A-G

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.4745T>C(p.Ile1582Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.011 in 1,614,106 control chromosomes in the GnomAD database, including 134 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0071 (3 hom., cov: 32)
  • Exomes 𝑓: 0.011 (131 hom.)
• Consequence: IFT172 NM_015662.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0930

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]

KRTCAP3 (HGNC:28943): (keratinocyte associated protein 3) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0050986707).
• BP6: Variant 2-27446270-A-G is Benign according to our data. Variant chr2-27446270-A-G is described in ClinVar as [Benign]. Clinvar id is 379765.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-27446270-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00712 (1084/152314) while in subpopulation NFE AF= 0.0125 (849/68026). AF 95% confidence interval is 0.0118. There are 3 homozygotes in gnomad4. There are 483 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IFT172	NM_015662.3	c.4745T>C	p.Ile1582Thr	missense_variant	43/48	ENST00000260570.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFT172	ENST00000260570.8	c.4745T>C	p.Ile1582Thr	missense_variant	43/48	1	NM_015662.3	P1

Frequencies

GnomAD3 genomes AF: 0.00712 AC: 1083 AN: 152196 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00251

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00399

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00746

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0125

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00768 AC: 1931 AN: 251446 Hom.: 20 AF XY: 0.00804 AC XY: 1092 AN XY: 135890

Gnomad AFR exome AF: 0.00172

Gnomad AMR exome AF: 0.00402

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00758

Gnomad FIN exome AF: 0.00286

Gnomad NFE exome AF: 0.0124

Gnomad OTH exome AF: 0.00701

GnomAD4 exome AF: 0.0114 AC: 16714 AN: 1461792 Hom.: 131 Cov.: 31 AF XY: 0.0113 AC XY: 8222 AN XY: 727186

Gnomad4 AFR exome AF: 0.00173

Gnomad4 AMR exome AF: 0.00423

Gnomad4 ASJ exome AF: 0.000995

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00777

Gnomad4 FIN exome AF: 0.00352

Gnomad4 NFE exome AF: 0.0136

Gnomad4 OTH exome AF: 0.00793

GnomAD4 genome AF: 0.00712 AC: 1084 AN: 152314 Hom.: 3 Cov.: 32 AF XY: 0.00649 AC XY: 483 AN XY: 74474

Gnomad4 AFR AF: 0.00250

Gnomad4 AMR AF: 0.00405

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00767

Gnomad4 FIN AF: 0.00179

Gnomad4 NFE AF: 0.0125

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.0109 Hom.: 16

Bravo AF: 0.00704

TwinsUK AF: 0.0132 AC: 49

ALSPAC AF: 0.0153 AC: 59

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.0121 AC: 104

ExAC AF: 0.00842 AC: 1022

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0102

EpiControl AF: 0.00996

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 17, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 21, 2018	- -

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

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2024

IFT172: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.76
Cadd	Benign	7.3
Dann	Benign	0.70
DEOGEN2	Benign	0.16	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0051	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.35	N
MutationTaster	Benign	0.90	N;D
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.060
Sift	Benign	0.62	T
Sift4G	Benign	0.72	T
Polyphen		0.0	B
Vest4		0.15
MVP		0.040
MPC		0.23
ClinPred		0.0028	T
GERP RS		-3.8
Varity_R		0.058
gMVP		0.16

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: rs61742074; hg19: chr2-27669137; COSMIC: COSV99274937; COSMIC: COSV99274937;