rs1423102192

Variant names:

• chr16-1526594-C-T
• rs1423102192
• NM_014714.4:c.2577+25G>A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3 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 (★★). ClinVar reports functional evidence for this variant: "SCV005400148: Immunofluorescence studies in patient cells have shown that this variant leads to a significant decrease in cilium formation and the mislocalisation of IFT140 protein (PMID:29688594)." and additional evidence is available in ClinVar.

• 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:5
• Conservation: PhyloP100: -0.392
• Publications: 0 publications found

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]

IFT140 Gene-Disease associations (from GenCC):

• autosomal dominant polycystic kidney disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics, ClinGen
• IFT140-related recessive ciliopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, Illumina
• short-rib thoracic dysplasia 9 with or without polydactyly

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet
• retinitis pigmentosa 80

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Leber congenital amaurosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Jeune syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV005400148: Immunofluorescence studies in patient cells have shown that this variant leads to a significant decrease in cilium formation and the mislocalisation of IFT140 protein (PMID: 29688594).; SCV002015023: "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." Geoffroy_2018
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 523178.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014714.4. 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
	IFT140	NM_014714.4	MANE Select	c.2577+25G>A		intron	N/A	NP_055529.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFT140	ENST00000426508.7	TSL:5 MANE Select	c.2577+25G>A		intron	N/A	ENSP00000406012.2	Q96RY7-1
	IFT140	ENST00000361339.9	TSL:1	c.159+25G>A		intron	N/A	ENSP00000354895.5	Q96RY7-2
	IFT140	ENST00000889170.1		c.2577+25G>A		intron	N/A	ENSP00000559229.1

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

African (AFR) AF: 0.00 AC: 0 AN: 29848

American (AMR) AF: 0.00 AC: 0 AN: 29088

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20930

East Asian (EAS) AF: 0.00 AC: 0 AN: 36700

South Asian (SAS) AF: 0.00 AC: 0 AN: 72190

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33512

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4122

European-Non Finnish (NFE) AF: 0.00000188 AC: 2 AN: 1066428

Other (OTH) AF: 0.00 AC: 0 AN: 55788

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Saldino-Mainzer syndrome (3)
1	-	-	Retinitis pigmentosa (1)
1	-	-	Saldino-Mainzer syndrome;C4540439:Retinitis pigmentosa 80 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	23
DANN	Benign	0.61
PhyloP100		-0.39
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Mutation Taster		=36/64	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1423102192; hg19: chr16-1576595;