chr2-27470935-G-C

Variant names:

• chr2-27470935-G-C
• rs61743977
• NM_015662.3:c.1685C>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_015662.3(IFT172):​c.1685C>G​(p.Thr562Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00604 in 1,603,214 control chromosomes in the GnomAD database, including 59 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0049 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0062 (55 hom.)
• Consequence: IFT172 NM_015662.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 9.14
• Publications: 8 publications found

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]

IFT172 Gene-Disease associations (from GenCC):

• ciliopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• short-rib thoracic dysplasia 10 with or without polydactyly

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• Bardet-Biedl syndrome 20

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• retinitis pigmentosa 71

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Bardet-Biedl syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Jeune syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• short-rib thoracic dysplasia 9 with or without polydactyly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 2-27470935-G-C is Benign according to our data. Variant chr2-27470935-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 476042.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00488 (743/152240) while in subpopulation NFE AF = 0.00701 (477/68018). AF 95% confidence interval is 0.00649. There are 4 homozygotes in GnomAd4. There are 362 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015662.3. 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
	IFT172	NM_015662.3	MANE Select	c.1685C>G	p.Thr562Ser	missense	Exon 16 of 48	NP_056477.1	Q9UG01-1
	IFT172	NM_001410739.1		c.1619C>G	p.Thr540Ser	missense	Exon 16 of 48	NP_001397668.1	A0A6Q8PGJ2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFT172	ENST00000260570.8	TSL:1 MANE Select	c.1685C>G	p.Thr562Ser	missense	Exon 16 of 48	ENSP00000260570.3	Q9UG01-1
	IFT172	ENST00000945698.1		c.1685C>G	p.Thr562Ser	missense	Exon 16 of 48	ENSP00000615757.1
	IFT172	ENST00000675690.1		c.1619C>G	p.Thr540Ser	missense	Exon 16 of 48	ENSP00000502283.1	A0A6Q8PGJ2

Frequencies

GnomAD3 genomes AF: 0.00488 AC: 742 AN: 152122 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00380

Gnomad ASJ AF: 0.0196

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00621

Gnomad FIN AF: 0.00349

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.00701

Gnomad OTH AF: 0.00669

GnomAD2 exomes AF: 0.00650 AC: 1565 AN: 240620 AF XY: 0.00686

Gnomad AFR exome AF: 0.000997

Gnomad AMR exome AF: 0.00407

Gnomad ASJ exome AF: 0.0217

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00295

Gnomad NFE exome AF: 0.00801

Gnomad OTH exome AF: 0.00921

GnomAD4 exome AF: 0.00617 AC: 8948 AN: 1450974 Hom.: 55 Cov.: 30 AF XY: 0.00636 AC XY: 4590 AN XY: 721596

African (AFR) AF: 0.00103 AC: 34 AN: 32894

American (AMR) AF: 0.00456 AC: 189 AN: 41450

Ashkenazi Jewish (ASJ) AF: 0.0219 AC: 561 AN: 25598

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39486

South Asian (SAS) AF: 0.00818 AC: 690 AN: 84330

European-Finnish (FIN) AF: 0.00321 AC: 171 AN: 53286

Middle Eastern (MID) AF: 0.0378 AC: 216 AN: 5718

European-Non Finnish (NFE) AF: 0.00597 AC: 6615 AN: 1108244

Other (OTH) AF: 0.00785 AC: 471 AN: 59968

GnomAD4 genome AF: 0.00488 AC: 743 AN: 152240 Hom.: 4 Cov.: 32 AF XY: 0.00486 AC XY: 362 AN XY: 74440

African (AFR) AF: 0.000963 AC: 40 AN: 41524

American (AMR) AF: 0.00379 AC: 58 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0196 AC: 68 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00642 AC: 31 AN: 4828

European-Finnish (FIN) AF: 0.00349 AC: 37 AN: 10602

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.00701 AC: 477 AN: 68018

Other (OTH) AF: 0.00662 AC: 14 AN: 2116

Alfa AF: 0.00770 Hom.: 4

Bravo AF: 0.00502

TwinsUK AF: 0.00782 AC: 29

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.00651 AC: 56

ExAC AF: 0.00698 AC: 847

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	not specified (4)
-	-	1	Oligodontia-cancer predisposition syndrome (1)
-	-	1	Short-rib thoracic dysplasia 10 with or without polydactyly;C4225342:Retinitis pigmentosa 71 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	21
DANN	Benign	0.91
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.19
Eigen_PC	Benign	0.065
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.68	T
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.55	N
PhyloP100		9.1
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.26	N
REVEL	Benign	0.16
Sift	Benign	0.39	T
Sift4G	Benign	0.14	T
Polyphen		0.0020	B
Vest4		0.093
MutPred		0.41		Loss of sheet (P = 0.0817)
MVP		0.11
MPC		0.16
ClinPred		0.048	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.075
gMVP		0.17
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.22		Position offset: -7

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs61743977; hg19: chr2-27693802; COSMIC: COSV107287911;