13-20574386-A-G

Variant names:

• chr13-20574386-A-G
• rs191277814
• NM_006531.5:c.1A>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PVS1_Supporting PM2

The NM_006531.5(IFT88):​c.1A>G​(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.0000598 in 1,606,362 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 0.000098 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000056 (0 hom.)
• Consequence: IFT88 NM_006531.5 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 3 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 2 codons. Genomic position: 20574389. Lost 0.002 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IFT88	NM_006531.5	c.1A>G	p.Met1?	start_lost	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.1A>G	p.Met1?	start_lost	Exon 2 of 26	1	NM_006531.5	ENSP00000261632.5
IFT88	ENST00000319980.10	c.28A>G	p.Met10Val	missense_variant	Exon 4 of 28	1		ENSP00000323580.6
IFT88	ENST00000389373.3	c.1A>G	p.Met1?	start_lost	Exon 3 of 4	4		ENSP00000374024.3

Frequencies

GnomAD3 genomes AF: 0.0000985 AC: 15 AN: 152232 Hom.: 0 Cov.: 32

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: 0.00

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000152 AC: 38 AN: 249890 Hom.: 0 AF XY: 0.000155 AC XY: 21 AN XY: 135130

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: 0.00

Gnomad FIN exome AF: 0.00139

Gnomad NFE exome AF: 0.0000618

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000557 AC: 81 AN: 1454012 Hom.: 0 Cov.: 28 AF XY: 0.0000608 AC XY: 44 AN XY: 723634

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: 0.00

Gnomad4 FIN exome AF: 0.00132

Gnomad4 NFE exome AF: 0.00000723

Gnomad4 OTH exome AF: 0.0000499

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152350 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74512

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00141

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000547 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000988 AC: 12

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Nov 11, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 10 of the IFT88 protein (p.Met10Val). This variant is present in population databases (rs191277814, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with IFT88-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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
BayesDel_addAF	Uncertain	0.087	D
BayesDel_noAF	Uncertain	0.070
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	.;T;.
Eigen	Benign	0.030
Eigen_PC	Benign	0.21
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;T;D
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.10	T;T;T
MetaSVM	Uncertain	-0.0047	T
MutationAssessor	Uncertain	2.2	.;M;.
PROVEAN	Benign	-0.73	N;N;N
REVEL	Uncertain	0.48
Sift	Uncertain	0.013	D;D;D
Sift4G	Pathogenic	0.0	D;T;D
Polyphen		0.034	.;B;.
Vest4		0.82
MVP		0.80
MPC		0.077
ClinPred		0.12	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs191277814; hg19: chr13-21148525;