rs138364426

Positions:

• chr16-1519871-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_014714.4(IFT140):​c.4040+10C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00449 in 1,522,378 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0055 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0044 (28 hom.)
• Consequence: IFT140 NM_014714.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.341

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 16-1519871-G-A is Benign according to our data. Variant chr16-1519871-G-A is described in ClinVar as [Benign]. Clinvar id is 196178.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1519871-G-A is described in Lovd as [Benign]. Variant chr16-1519871-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00547 (832/152140) while in subpopulation SAS AF= 0.0104 (50/4810). AF 95% confidence interval is 0.00831. There are 2 homozygotes in gnomad4. There are 390 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IFT140	NM_014714.4	c.4040+10C>T		intron_variant		ENST00000426508.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFT140	ENST00000426508.7	c.4040+10C>T		intron_variant		5	NM_014714.4	P1

Frequencies

GnomAD3 genomes AF: 0.00548 AC: 833 AN: 152022 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00909

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0102

Gnomad FIN AF: 0.00207

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00453

Gnomad OTH AF: 0.00672

GnomAD3 exomes AF: 0.00403 AC: 723 AN: 179354 Hom.: 3 AF XY: 0.00416 AC XY: 398 AN XY: 95680

Gnomad AFR exome AF: 0.00943

Gnomad AMR exome AF: 0.00185

Gnomad ASJ exome AF: 0.00125

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00891

Gnomad FIN exome AF: 0.000557

Gnomad NFE exome AF: 0.00424

Gnomad OTH exome AF: 0.00441

GnomAD4 exome AF: 0.00438 AC: 5999 AN: 1370238 Hom.: 28 Cov.: 31 AF XY: 0.00457 AC XY: 3077 AN XY: 672698

Gnomad4 AFR exome AF: 0.00885

Gnomad4 AMR exome AF: 0.00184

Gnomad4 ASJ exome AF: 0.000539

Gnomad4 EAS exome AF: 0.0000516

Gnomad4 SAS exome AF: 0.0103

Gnomad4 FIN exome AF: 0.000883

Gnomad4 NFE exome AF: 0.00432

Gnomad4 OTH exome AF: 0.00402

GnomAD4 genome AF: 0.00547 AC: 832 AN: 152140 Hom.: 2 Cov.: 33 AF XY: 0.00524 AC XY: 390 AN XY: 74370

Gnomad4 AFR AF: 0.00906

Gnomad4 AMR AF: 0.00262

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0104

Gnomad4 FIN AF: 0.00207

Gnomad4 NFE AF: 0.00452

Gnomad4 OTH AF: 0.00665

Alfa AF: 0.00517 Hom.: 2

Bravo AF: 0.00550

Asia WGS AF: 0.00549 AC: 19 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 09, 2014	- -

Saldino-Mainzer syndrome Benign:2

Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.6
DANN	Benign	0.40
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs138364426; hg19: chr16-1569872;