rs746697405

chr16-1519960-TCTTGGC-Tchr16-1519960-TCTTGGC-TCTTGGCCTTGGC

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP3 BS1_Supporting

The NM_014714.4(IFT140):c.3955_3960del(p.Ala1319_Lys1320del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00205 in 1,607,122 control chromosomes in the GnomAD database, including 8 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (7 hom.)
• Consequence: IFT140 NM_014714.4 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:6 B:1
• Conservation: PhyloP100: 2.37

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 Likely_benign. Variant got -2 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_014714.4
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00212 (3086/1454760) while in subpopulation NFE AF= 0.00253 (2804/1109372). AF 95% confidence interval is 0.00245. There are 7 homozygotes in gnomad4_exome. There are 1508 alleles in male gnomad4_exome subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IFT140	NM_014714.4	c.3955_3960del	p.Ala1319_Lys1320del	inframe_deletion	29/31	ENST00000426508.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFT140	ENST00000426508.7	c.3955_3960del	p.Ala1319_Lys1320del	inframe_deletion	29/31	5	NM_014714.4	P1

Frequencies

GnomAD3 genomes AF: 0.00133 AC: 203 AN: 152244 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000675

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00222

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00109 AC: 267 AN: 244378 Hom.: 1 AF XY: 0.00111 AC XY: 147 AN XY: 132404

Gnomad AFR exome AF: 0.000684

Gnomad AMR exome AF: 0.000757

Gnomad ASJ exome AF: 0.00356

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000337

Gnomad FIN exome AF: 0.0000944

Gnomad NFE exome AF: 0.00169

Gnomad OTH exome AF: 0.00102

GnomAD4 exome AF: 0.00212 AC: 3086 AN: 1454760 Hom.: 7 AF XY: 0.00208 AC XY: 1508 AN XY: 723680

Gnomad4 AFR exome AF: 0.000637

Gnomad4 AMR exome AF: 0.000814

Gnomad4 ASJ exome AF: 0.00316

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000586

Gnomad4 FIN exome AF: 0.000283

Gnomad4 NFE exome AF: 0.00253

Gnomad4 OTH exome AF: 0.00200

GnomAD4 genome AF: 0.00133 AC: 203 AN: 152362 Hom.: 1 Cov.: 32 AF XY: 0.00119 AC XY: 89 AN XY: 74516

Gnomad4 AFR AF: 0.000673

Gnomad4 AMR AF: 0.000914

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00222

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000838 Hom.: 0

Bravo AF: 0.00135

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:6 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Saldino-Mainzer syndrome Uncertain:2 Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Apr 04, 2024	- -

Orofacial-digital syndrome III;C4551856:Asphyxiating thoracic dystrophy 1 Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Department Of Translational Genomics (developmental Genetics Section), King Faisal Specialist Hospital & Research Centre

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Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 12, 2023

The c.3955_3960delGCCAAG (p.A1319_K1320del) alteration is located in exon 29 (coding exon 27) of the IFT140 gene. This alteration consists of an in-frame deletion of 6 nucleotides between nucleotide positions c.3955 and c.3960, resulting in the deletion of 2 residues. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs746697405; hg19: chr16-1569961;