rs150014480

chr16-1592264-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_014714.4(IFT140):c.546C>T(p.Asp182=) variant causes a synonymous change. The variant allele was found at a frequency of 0.000919 in 1,614,152 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00089 (21 hom.)
• Consequence: IFT140 NM_014714.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 3.67

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 16-1592264-G-A is Benign according to our data. Variant chr16-1592264-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 318210.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=1, Likely_benign=1}. Variant chr16-1592264-G-A is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IFT140	NM_014714.4	c.546C>T	p.Asp182=	synonymous_variant	6/31	ENST00000426508.7
LOC105371046	NR_135176.1	n.59+11679G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFT140	ENST00000426508.7	c.546C>T	p.Asp182=	synonymous_variant	6/31	5	NM_014714.4	P1
	ENST00000563162.1	n.59+11679G>A		intron_variant, non_coding_transcript_variant		2
IFT140	ENST00000439987.6	n.607C>T		non_coding_transcript_exon_variant	5/19	2
IFT140	ENST00000397417.6	c.329-7844C>T		intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00116 AC: 176 AN: 152164 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.0416

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00181 AC: 456 AN: 251488 Hom.: 8 AF XY: 0.00161 AC XY: 219 AN XY: 135920

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.0364

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000510

Gnomad OTH exome AF: 0.00293

GnomAD4 exome AF: 0.000895 AC: 1308 AN: 1461870 Hom.: 21 Cov.: 32 AF XY: 0.000916 AC XY: 666 AN XY: 727226

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000335

Gnomad4 ASJ exome AF: 0.0343

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000196

Gnomad4 OTH exome AF: 0.00273

GnomAD4 genome AF: 0.00116 AC: 176 AN: 152282 Hom.: 3 Cov.: 32 AF XY: 0.00121 AC XY: 90 AN XY: 74460

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.0416

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00324 Hom.: 6

Bravo AF: 0.00124

EpiCase AF: 0.00115

EpiControl AF: 0.000711

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Saldino-Mainzer syndrome Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -

IFT140-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 15, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2023

IFT140: BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
Cadd	Benign	8.5
Dann	Benign	0.77
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs150014480; hg19: chr16-1642265;