13-20631053-G-C

Variant names:

• chr13-20631053-G-C
• rs9509307
• NM_006531.5:c.1337G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006531.5(IFT88):​c.1337G>C​(p.Ser446Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. S446N) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: IFT88 NM_006531.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.19
• Publications: 42 publications found

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]

IFT88 Gene-Disease associations (from GenCC):

• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39128712).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006531.5. 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
	IFT88	NM_006531.5	MANE Select	c.1337G>C	p.Ser446Thr	missense	Exon 16 of 26	NP_006522.2
	IFT88	NM_001318493.2		c.1364G>C	p.Ser455Thr	missense	Exon 17 of 27	NP_001305422.1	Q13099-1
	IFT88	NM_001353565.2		c.1364G>C	p.Ser455Thr	missense	Exon 17 of 27	NP_001340494.1	Q13099-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFT88	ENST00000351808.10	TSL:1 MANE Select	c.1337G>C	p.Ser446Thr	missense	Exon 16 of 26	ENSP00000261632.5	Q13099-2
	IFT88	ENST00000319980.10	TSL:1	c.1364G>C	p.Ser455Thr	missense	Exon 18 of 28	ENSP00000323580.6	Q13099-1
	IFT88	ENST00000894242.1		c.1337G>C	p.Ser446Thr	missense	Exon 17 of 27	ENSP00000564301.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.19	T
Eigen	Benign	0.042
Eigen_PC	Benign	0.19
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	1.7	L
PhyloP100		6.2
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.054
Sift	Benign	0.33	T
Sift4G	Benign	0.30	T
Polyphen		0.0040	B
Vest4		0.19
MutPred		0.30		Gain of catalytic residue at V457 (P = 0.0663)
MVP		0.56
MPC		0.048
ClinPred		0.82	D
GERP RS		4.6
Varity_R		0.25
gMVP		0.36
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs9509307; hg19: chr13-21205192;