rs2442455

chr13-20615802-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006531.5(IFT88):c.1122G>A(p.Met374Ile) variant causes a missense change. The variant allele was found at a frequency of 0.137 in 1,587,320 control chromosomes in the GnomAD database, including 16,673 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M374K) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.16 (2394 hom., cov: 32)
  • Exomes 𝑓: 0.13 (14279 hom.)
• Consequence: IFT88 NM_006531.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.19

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013180673).
• BP6: Variant 13-20615802-G-A is Benign according to our data. Variant chr13-20615802-G-A is described in ClinVar as [Benign]. Clinvar id is 402965.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.248 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IFT88	NM_006531.5	c.1122G>A	p.Met374Ile	missense_variant	14/26	ENST00000351808.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFT88	ENST00000351808.10	c.1122G>A	p.Met374Ile	missense_variant	14/26	1	NM_006531.5	P1

Frequencies

GnomAD3 genomes AF: 0.164 AC: 24962 AN: 151888 Hom.: 2394 Cov.: 32

Gnomad AFR AF: 0.252

Gnomad AMI AF: 0.113

Gnomad AMR AF: 0.125

Gnomad ASJ AF: 0.168

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0634

Gnomad FIN AF: 0.108

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.149

Gnomad OTH AF: 0.144

GnomAD3 exomes AF: 0.126 AC: 30213 AN: 239968 Hom.: 2392 AF XY: 0.125 AC XY: 16222 AN XY: 129786

Gnomad AFR exome AF: 0.252

Gnomad AMR exome AF: 0.0857

Gnomad ASJ exome AF: 0.166

Gnomad EAS exome AF: 0.0000569

Gnomad SAS exome AF: 0.0735

Gnomad FIN exome AF: 0.112

Gnomad NFE exome AF: 0.151

Gnomad OTH exome AF: 0.136

GnomAD4 exome AF: 0.134 AC: 193041 AN: 1435314 Hom.: 14279 Cov.: 27 AF XY: 0.133 AC XY: 94966 AN XY: 714680

Gnomad4 AFR exome AF: 0.252

Gnomad4 AMR exome AF: 0.0909

Gnomad4 ASJ exome AF: 0.166

Gnomad4 EAS exome AF: 0.000280

Gnomad4 SAS exome AF: 0.0780

Gnomad4 FIN exome AF: 0.113

Gnomad4 NFE exome AF: 0.142

Gnomad4 OTH exome AF: 0.133

GnomAD4 genome AF: 0.164 AC: 24979 AN: 152006 Hom.: 2394 Cov.: 32 AF XY: 0.158 AC XY: 11715 AN XY: 74318

Gnomad4 AFR AF: 0.252

Gnomad4 AMR AF: 0.125

Gnomad4 ASJ AF: 0.168

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0635

Gnomad4 FIN AF: 0.108

Gnomad4 NFE AF: 0.149

Gnomad4 OTH AF: 0.143

Alfa AF: 0.149 Hom.: 4501

Bravo AF: 0.170

TwinsUK AF: 0.132 AC: 490

ALSPAC AF: 0.148 AC: 571

ESP6500AA AF: 0.248 AC: 1094

ESP6500EA AF: 0.147 AC: 1264

ExAC AF: 0.132 AC: 15962

Asia WGS AF: 0.0400 AC: 140 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	22
Dann	Uncertain	0.99
Eigen	Benign	-0.090
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.97	D;D
MetaRNN	Benign	0.0013	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.097	P;P;P;P
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.99	N;N
REVEL	Benign	0.011
Sift	Benign	0.18	T;T
Sift4G	Benign	0.19	T;T
Polyphen		0.023	.;B
Vest4		0.17
MutPred		0.34		.;Loss of disorder (P = 0.0696);
MPC		0.048
ClinPred		0.0065	T
GERP RS		4.7
Varity_R		0.15
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.27		Position offset: -9

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

Publications

LitVar

Other links and lift over

dbSNP: rs2442455; hg19: chr13-21189941; COSMIC: COSV60673403; COSMIC: COSV60673403;