rs1423102192

Positions:

• chr16-1526594-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_014714.4(IFT140):​c.2577+25G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000148 in 1,348,606 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: IFT140 NM_014714.4 intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: -0.392

Genes affected

IFT140 (HGNC:29077): (intraflagellar transport 140) This gene encodes one of the subunits of the intraflagellar transport (IFT) complex A. Intraflagellar transport is involved in the genesis, resorption and signaling of primary cilia. The primary cilium is a microtubule-based sensory organelle at the surface of most quiescent mammalian cells, that receives signals from its environment, such as the flow of fluid, light or odors, and transduces those signals to the nucleus. Loss of the corresponding protein in mouse results in renal cystic disease. [provided by RefSeq, Jun 2012]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 16-1526594-C-T is Pathogenic according to our data. Variant chr16-1526594-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 523178.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IFT140	NM_014714.4	c.2577+25G>A		intron_variant		ENST00000426508.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFT140	ENST00000426508.7	c.2577+25G>A		intron_variant		5	NM_014714.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000148 AC: 2 AN: 1348606 Hom.: 0 Cov.: 31 AF XY: 0.00000151 AC XY: 1 AN XY: 662694

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: 0.00

Gnomad4 NFE exome AF: 0.00000188

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Saldino-Mainzer syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Laboratory of Medical Genetics (UMR_S 1112), INSERM/Strasbourg University

Jan 01, 2018

- -

Retinitis pigmentosa Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 22, 2021

Variant summary: IFT140 c.2577+25G>A is located at a position not widely known to affect splicing. Several computational tools predict a significant impact on normal splicing: One predict the variant weakens a 5' donor site. Three predict the variant strengthens a cryptic 5' donor site. One predict the variant creates a 5' donor site. Patient RNA analysis confirmed that a novel donor splice site within the intron 20 resulted in the incorporation of 21 additional base pairs (r.2577_2578insGTGAGGGGCGCCCGCCATGGG) that are predicted to add seven new amino acids to the protein sequence (p.Leu859_Glu860insValArgGlyAlaArgHisGly; Geoffroy_2018). The variant was absent in 125168 control chromosomes. c.2577+25G>A has been reported in the literature in two siblings affected with retinitis pigmentosa, short stature, brachydactyly, moderate renal failure and overweight (Geoffroy_2018). In this same study, functional analysis on the patients cells further revealed a reduced level of ciliated cells and mislocalization of the IFT140 mutant away from the cilia base. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	23
DANN	Benign	0.61
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.83		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.83		Position offset: 4

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

Publications

LitVar

Other links and lift over

dbSNP: rs1423102192; hg19: chr16-1576595;