rs431905522

Variant names:

• chr16-1583365-CG-C
• rs431905522
• NM_014714.4:c.1380delC

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_014714.4(IFT140):​c.1380delC​(p.Asn460LysfsTer28) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. N460N) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IFT140 NM_014714.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 0.216
• Publications: 3 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: Labcorp Genetics (formerly Invitae), G2P, 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

ENSG00000260989 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-1583365-CG-C is Pathogenic according to our data. Variant chr16-1583365-CG-C is described in ClinVar as Pathogenic. ClinVar VariationId is 97055.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IFT140	NM_014714.4	c.1380delC	p.Asn460LysfsTer28	frameshift_variant	Exon 12 of 31	ENST00000426508.7	NP_055529.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IFT140	ENST00000426508.7	c.1380delC	p.Asn460LysfsTer28	frameshift_variant	Exon 12 of 31	5	NM_014714.4	ENSP00000406012.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251220 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Saldino-Mainzer syndrome Pathogenic:2

May 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Feb 09, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This premature translational stop signal has been observed in individual(s) with asphyxiating thoracic dystrophy (PMID: 23418020). This variant is present in population databases (rs431905522, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Asn460Lysfs*28) in the IFT140 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in IFT140 are known to be pathogenic (PMID: 22503633, 23418020, 24009529, 26216056). ClinVar contains an entry for this variant (Variation ID: 97055). For these reasons, this variant has been classified as Pathogenic. -

Saldino-Mainzer syndrome;C4540439:Retinitis pigmentosa 80 Pathogenic:1

May 17, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Renal cyst Pathogenic:1

Oct 10, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with retinitis pigmentosa 80 (MIM#617781), short-rib thoracic dysplasia 9 with or without polydactyly (MIM#266920) and cystic kidney disease (MONDO:0002473), IFT140-related (PMID: 34890546). (I) 0108 - This gene is associated with both recessive and dominant disease. Retinitis pigmentosa 80 (MIM#617781) and short-rib thoracic dysplasia 9 with or without polydactyly (MIM#266920) are inherited in an autosomal recessive manner, while cystic kidney disease (MONDO:0002473), IFT140-related is inherited in an autosomal dominant manner (OMIM, PMID: 34890546). (I) 0112 - The dominant condition associated with this gene may have incomplete penetrance. Parents of children with short-rib thoracic dysplasia 9 with or without polydactyly, who carry a single pathogenic variant that has also previously been associated with the dominant cystic kidney disease phenotype, have been reported as unaffected (PMID: 34890546). However, these parents weren't specifically assessed for cystic kidney disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v2: 1 heterozygote, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). These variants have been reported in families with later onset autosomal dominant polycystic kidney disease (PMID: 34890546) and autosomal recessive IFT140-related conditions (PMIDs: 22503633, 26968735). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. It has been observed in a compound heterozygous individual with Jeune asphyxiating thoracic dystrophy with severe kidney involvement and retinal disease (PMID: 23418020). In addition, it has been reported as pathogenic by two clinical laboratories (ClinVar). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.22
Mutation Taster		=3/197	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs431905522; hg19: chr16-1633366;