rs4786350

Positions:

• chr16-1587999-C-G
• chr16-1587999-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014714.4(IFT140):​c.836G>C​(p.Arg279Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0443 in 1,613,380 control chromosomes in the GnomAD database, including 2,167 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.043 (248 hom., cov: 32)
  • Exomes 𝑓: 0.044 (1919 hom.)
• Consequence: IFT140 NM_014714.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.279

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017949343).
• BP6: Variant 16-1587999-C-G is Benign according to our data. Variant chr16-1587999-C-G is described in ClinVar as [Benign]. Clinvar id is 129262.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1587999-C-G is described in Lovd as [Benign]. Variant chr16-1587999-C-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.074 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IFT140	NM_014714.4	c.836G>C	p.Arg279Pro	missense_variant	8/31	ENST00000426508.7	NP_055529.2
LOC105371046	NR_135176.1	n.59+7414C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IFT140	ENST00000426508.7	c.836G>C	p.Arg279Pro	missense_variant	8/31	5	NM_014714.4	ENSP00000406012	P1
	ENST00000563162.1	n.59+7414C>G		intron_variant, non_coding_transcript_variant		2
IFT140	ENST00000439987.6	n.897G>C		non_coding_transcript_exon_variant	7/19	2
IFT140	ENST00000397417.6	c.329-3579G>C		intron_variant, NMD_transcript_variant		5		ENSP00000380562

Frequencies

GnomAD3 genomes AF: 0.0425 AC: 6471 AN: 152122 Hom.: 248 Cov.: 32

Gnomad AFR AF: 0.00900

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0772

Gnomad ASJ AF: 0.0179

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0139

Gnomad FIN AF: 0.141

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0472

Gnomad OTH AF: 0.0340

GnomAD3 exomes AF: 0.0500 AC: 12510 AN: 250286 Hom.: 552 AF XY: 0.0471 AC XY: 6378 AN XY: 135344

Gnomad AFR exome AF: 0.00754

Gnomad AMR exome AF: 0.102

Gnomad ASJ exome AF: 0.0142

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0168

Gnomad FIN exome AF: 0.133

Gnomad NFE exome AF: 0.0448

Gnomad OTH exome AF: 0.0487

GnomAD4 exome AF: 0.0444 AC: 64918 AN: 1461140 Hom.: 1919 Cov.: 30 AF XY: 0.0437 AC XY: 31772 AN XY: 726864

Gnomad4 AFR exome AF: 0.00753

Gnomad4 AMR exome AF: 0.104

Gnomad4 ASJ exome AF: 0.0155

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.0166

Gnomad4 FIN exome AF: 0.128

Gnomad4 NFE exome AF: 0.0440

Gnomad4 OTH exome AF: 0.0396

GnomAD4 genome AF: 0.0426 AC: 6480 AN: 152240 Hom.: 248 Cov.: 32 AF XY: 0.0462 AC XY: 3442 AN XY: 74428

Gnomad4 AFR AF: 0.00900

Gnomad4 AMR AF: 0.0777

Gnomad4 ASJ AF: 0.0179

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0141

Gnomad4 FIN AF: 0.141

Gnomad4 NFE AF: 0.0472

Gnomad4 OTH AF: 0.0336

Alfa AF: 0.0250 Hom.: 25

Bravo AF: 0.0361

TwinsUK AF: 0.0415 AC: 154

ALSPAC AF: 0.0397 AC: 153

ESP6500AA AF: 0.00773 AC: 34

ESP6500EA AF: 0.0442 AC: 380

ExAC AF: 0.0452 AC: 5492

Asia WGS AF: 0.00924 AC: 32 AN: 3478

EpiCase AF: 0.0406

EpiControl AF: 0.0380

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Saldino-Mainzer syndrome Benign:4

Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jan 12, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
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. -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 06, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

-

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.16
DANN	Benign	0.71
DEOGEN2	Benign	0.0036	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.58	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.20	T
PROVEAN	Benign	0.11	N
REVEL	Benign	0.036
Sift	Benign	0.34	T
Sift4G	Benign	0.35	T
Polyphen		0.0	B
Vest4		0.077
MPC		0.097
ClinPred		0.010	T
GERP RS		-11
Varity_R		0.079
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs4786350; hg19: chr16-1638000;