chr2-27444478-C-G

Variant names:

• chr2-27444478-C-G
• rs1238875084
• NM_015662.3:c.5204G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015662.3(IFT172):​c.5204G>C​(p.Ser1735Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,438 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1735N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: IFT172 NM_015662.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.96
• Publications: 0 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]

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12770358).

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.5204G>C	p.Ser1735Thr	missense	Exon 48 of 48	NP_056477.1	Q9UG01-1
	IFT172	NM_001410739.1		c.5138G>C	p.Ser1713Thr	missense	Exon 48 of 48	NP_001397668.1	A0A6Q8PGJ2
	KRTCAP3	NM_001168364.2		c.*5+417C>G		intron	N/A	NP_001161836.1	Q53RY4-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFT172	ENST00000260570.8	TSL:1 MANE Select	c.5204G>C	p.Ser1735Thr	missense	Exon 48 of 48	ENSP00000260570.3	Q9UG01-1
	IFT172	ENST00000509128.5	TSL:1	n.*649G>C		non_coding_transcript_exon	Exon 16 of 16	ENSP00000427255.1	H0YAI8
	IFT172	ENST00000509128.5	TSL:1	n.*649G>C		3_prime_UTR	Exon 16 of 16	ENSP00000427255.1	H0YAI8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461438 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726998

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86124

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111800

Other (OTH) AF: 0.00 AC: 0 AN: 60376

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	21
DANN	Benign	0.95
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.16
Eigen_PC	Benign	0.072
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.0093	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N
PhyloP100		3.0
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.84	N
REVEL	Benign	0.062
Sift	Benign	0.38	T
Sift4G	Benign	0.47	T
Polyphen		0.012	B
Vest4		0.13
MutPred		0.28		Gain of ubiquitination at K1732 (P = 0.0741)
MVP		0.27
MPC		0.17
ClinPred		0.50	D
GERP RS		5.6
Varity_R		0.21
gMVP		0.42
Mutation Taster		=79/21	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: rs1238875084; hg19: chr2-27667345;