chr13-20574456-A-G

Variant names:

• chr13-20574456-A-G
• rs1228511905
• NM_006531.5:c.71A>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006531.5(IFT88):​c.71A>G​(p.Asn24Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000437 in 1,600,902 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: IFT88 NM_006531.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.62

Genes affected

IFT88 (HGNC:20606): (intraflagellar transport 88) This gene encodes a member of the tetratrico peptide repeat (TPR) family. The encoded protein is involved in cilium biogenesis. Mutations of a similar gene in mouse can cause polycystic kidney disease. Several transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35279778).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IFT88	NM_006531.5	c.71A>G	p.Asn24Ser	missense_variant	Exon 2 of 26	ENST00000351808.10	NP_006522.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IFT88	ENST00000351808.10	c.71A>G	p.Asn24Ser	missense_variant	Exon 2 of 26	1	NM_006531.5	ENSP00000261632.5
IFT88	ENST00000319980.10	c.98A>G	p.Asn33Ser	missense_variant	Exon 4 of 28	1		ENSP00000323580.6
IFT88	ENST00000389373.3	c.71A>G	p.Asn24Ser	missense_variant	Exon 3 of 4	4		ENSP00000374024.3

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1448692 Hom.: 0 Cov.: 26 AF XY: 0.00000139 AC XY: 1 AN XY: 721250

Gnomad4 AFR exome AF: 0.0000301

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000182

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152210 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74360

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Sep 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.98A>G (p.N33S) alteration is located in exon 4 (coding exon 2) of the IFT88 gene. This alteration results from a A to G substitution at nucleotide position 98, causing the asparagine (N) at amino acid position 33 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Aug 18, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant has not been reported in the literature in individuals affected with IFT88-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.03%). This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 33 of the IFT88 protein (p.Asn33Ser). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	.;T;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.35	T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Uncertain	2.3	.;M;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.4	N;N;D
REVEL	Benign	0.18
Sift	Benign	0.16	T;T;D
Sift4G	Benign	0.17	T;T;D
Polyphen		0.96	.;P;.
Vest4		0.45
MutPred		0.45		.;Gain of catalytic residue at I35 (P = 0.0026);.;
MVP		0.40
MPC		0.16
ClinPred		0.94	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.10
gMVP		0.54

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: rs1228511905; hg19: chr13-21148595;