rs34668993

Positions:

• chr16-1526742-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_014714.4(IFT140):​c.2454C>T​(p.Asp818=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00709 in 1,609,832 control chromosomes in the GnomAD database, including 141 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (57 hom., cov: 33)
  • Exomes 𝑓: 0.0060 (84 hom.)
• Consequence: IFT140 NM_014714.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0220

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 16-1526742-G-A is Benign according to our data. Variant chr16-1526742-G-A is described in ClinVar as [Benign]. Clinvar id is 318056.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.022 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0507 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IFT140	NM_014714.4	c.2454C>T	p.Asp818=	synonymous_variant	20/31	ENST00000426508.7	NP_055529.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IFT140	ENST00000426508.7	c.2454C>T	p.Asp818=	synonymous_variant	20/31	5	NM_014714.4	ENSP00000406012	P1

Frequencies

GnomAD3 genomes AF: 0.0178 AC: 2710 AN: 152238 Hom.: 58 Cov.: 33

Gnomad AFR AF: 0.0516

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.00700

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0124

Gnomad FIN AF: 0.000941

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00500

Gnomad OTH AF: 0.0138

GnomAD3 exomes AF: 0.00774 AC: 1856 AN: 239762 Hom.: 31 AF XY: 0.00728 AC XY: 952 AN XY: 130716

Gnomad AFR exome AF: 0.0525

Gnomad AMR exome AF: 0.00449

Gnomad ASJ exome AF: 0.00123

Gnomad EAS exome AF: 0.000281

Gnomad SAS exome AF: 0.0119

Gnomad FIN exome AF: 0.000542

Gnomad NFE exome AF: 0.00460

Gnomad OTH exome AF: 0.00664

GnomAD4 exome AF: 0.00597 AC: 8706 AN: 1457476 Hom.: 84 Cov.: 32 AF XY: 0.00604 AC XY: 4380 AN XY: 724814

Gnomad4 AFR exome AF: 0.0527

Gnomad4 AMR exome AF: 0.00473

Gnomad4 ASJ exome AF: 0.000731

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.0119

Gnomad4 FIN exome AF: 0.00101

Gnomad4 NFE exome AF: 0.00466

Gnomad4 OTH exome AF: 0.00701

GnomAD4 genome AF: 0.0178 AC: 2709 AN: 152356 Hom.: 57 Cov.: 33 AF XY: 0.0172 AC XY: 1283 AN XY: 74494

Gnomad4 AFR AF: 0.0514

Gnomad4 AMR AF: 0.00699

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0126

Gnomad4 FIN AF: 0.000941

Gnomad4 NFE AF: 0.00498

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.0108 Hom.: 4

Bravo AF: 0.0193

Asia WGS AF: 0.00491 AC: 17 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Saldino-Mainzer syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	12
DANN	Benign	0.91
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: rs34668993; hg19: chr16-1576743;