rs34900355

chr16-1564056-G-A

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.2008C>T(p.Pro670Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00396 in 1,602,258 control chromosomes in the GnomAD database, including 217 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P670L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.020 (103 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (114 hom.)
• Consequence: IFT140 NM_014714.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.15

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 (MetaRNN=0.0036635995).
• BP6: Variant 16-1564056-G-A is Benign according to our data. Variant chr16-1564056-G-A is described in ClinVar as [Benign]. Clinvar id is 318182.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1564056-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0672 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IFT140	NM_014714.4	c.2008C>T	p.Pro670Ser	missense_variant	17/31	ENST00000426508.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFT140	ENST00000426508.7	c.2008C>T	p.Pro670Ser	missense_variant	17/31	5	NM_014714.4	P1

Frequencies

GnomAD3 genomes AF: 0.0203 AC: 3087 AN: 152226 Hom.: 103 Cov.: 32

Gnomad AFR AF: 0.0696

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00889

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.0148

GnomAD3 exomes AF: 0.00543 AC: 1355 AN: 249726 Hom.: 48 AF XY: 0.00399 AC XY: 539 AN XY: 135122

Gnomad AFR exome AF: 0.0707

Gnomad AMR exome AF: 0.00415

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000658

Gnomad FIN exome AF: 0.000324

Gnomad NFE exome AF: 0.000389

Gnomad OTH exome AF: 0.00443

GnomAD4 exome AF: 0.00225 AC: 3261 AN: 1449914 Hom.: 114 Cov.: 30 AF XY: 0.00190 AC XY: 1364 AN XY: 719328

Gnomad4 AFR exome AF: 0.0729

Gnomad4 AMR exome AF: 0.00468

Gnomad4 ASJ exome AF: 0.0000385

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000467

Gnomad4 FIN exome AF: 0.000357

Gnomad4 NFE exome AF: 0.000274

Gnomad4 OTH exome AF: 0.00487

GnomAD4 genome AF: 0.0203 AC: 3085 AN: 152344 Hom.: 103 Cov.: 32 AF XY: 0.0196 AC XY: 1458 AN XY: 74496

Gnomad4 AFR AF: 0.0694

Gnomad4 AMR AF: 0.00888

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000456

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.00878 Hom.: 13

Bravo AF: 0.0237

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0682 AC: 300

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00649 AC: 788

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Saldino-Mainzer syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 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:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 04, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	2.4
Dann	Benign	0.41
DEOGEN2	Benign	0.0088	T
Eigen	Benign	-0.94
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.24	T
MetaRNN	Benign	0.0037	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.68	N
REVEL	Benign	0.039
Sift	Benign	0.76	T
Sift4G	Benign	0.71	T
Polyphen		0.0	B
Vest4		0.065
MVP		0.61
MPC		0.069
ClinPred		0.0040	T
GERP RS		-0.37
Varity_R		0.029
gMVP		0.27

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: rs34900355; hg19: chr16-1614057;