20-43594802-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_016004.5(IFT52):c.104A>G(p.Asn35Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000122 in 1,567,538 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: IFT52 NM_016004.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.37

Genes affected

IFT52 (HGNC:15901): (intraflagellar transport 52) This gene encodes a conserved proline-rich protein that is a component of the intraflagellar transport-B (IFT-B) core complex. The encoded protein is essential for the integrity of the IFT-B core complex, and for biosynthesis and maintenance of cilia. Mutations in this gene are associated with ciliopathy that affects the skeleton. [provided by RefSeq, Oct 2016]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.013779283).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IFT52	NM_016004.5	c.104A>G	p.Asn35Ser	missense_variant	2/14	ENST00000373030.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFT52	ENST00000373030.8	c.104A>G	p.Asn35Ser	missense_variant	2/14	1	NM_016004.5	P1
IFT52	ENST00000373039.4	c.104A>G	p.Asn35Ser	missense_variant	2/14	5		P1
IFT52	ENST00000486243.1	n.81A>G		non_coding_transcript_exon_variant	1/3	5

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152186 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000207 AC: 52 AN: 251328 Hom.: 0 AF XY: 0.000272 AC XY: 37 AN XY: 135842

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00167

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000126 AC: 178 AN: 1415234 Hom.: 0 Cov.: 25 AF XY: 0.000175 AC XY: 124 AN XY: 707174

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00198

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000153

GnomAD4 genome AF: 0.0000919 AC: 14 AN: 152304 Hom.: 0 Cov.: 31 AF XY: 0.000134 AC XY: 10 AN XY: 74474

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000492 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.000239 AC: 29

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 07, 2023

This sequence change replaces asparagine with serine at codon 35 of the IFT52 protein (p.Asn35Ser). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and serine. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt IFT52 protein function. ClinVar contains an entry for this variant (Variation ID: 1386108). This variant has not been reported in the literature in individuals affected with IFT52-related conditions. This variant is present in population databases (rs567232435, gnomAD 0.2%). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	20
Dann	Benign	0.94
DEOGEN2	Benign	0.10	T;T
Eigen	Benign	-0.088
Eigen_PC	Benign	0.16
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.014	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.92	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.090	N;N
REVEL	Benign	0.056
Sift	Benign	0.75	T;T
Sift4G	Benign	0.81	T;T
Polyphen		0.0030	B;B
Vest4		0.16
MutPred		0.29		Gain of phosphorylation at N35 (P = 0.0154);Gain of phosphorylation at N35 (P = 0.0154);
MVP		0.65
MPC		0.15
ClinPred		0.18	T
GERP RS		5.8
Varity_R		0.058
gMVP		0.33

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: rs567232435; hg19: chr20-42223442;