16-1510942-C-T

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.*2G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000505 in 1,610,274 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00044 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00051 (6 hom.)
• Consequence: IFT140 NM_014714.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0990

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=-0.85).
• BP6: Variant 16-1510942-C-T is Benign according to our data. Variant chr16-1510942-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 281447.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00044 (67/152378) while in subpopulation SAS AF= 0.006 (29/4832). AF 95% confidence interval is 0.00429. There are 3 homozygotes in gnomad4. There are 43 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• 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.*2G>A		3_prime_UTR_variant	31/31	ENST00000426508.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFT140	ENST00000426508.7	c.*2G>A		3_prime_UTR_variant	31/31	5	NM_014714.4	P1
IFT140	ENST00000361339.9	c.*2G>A		3_prime_UTR_variant	13/13	1
IFT140	ENST00000565298.5	n.4215G>A		non_coding_transcript_exon_variant	19/19	2
IFT140	ENST00000397417.6	c.*2829G>A		3_prime_UTR_variant, NMD_transcript_variant	24/24	5

Frequencies

GnomAD3 genomes AF: 0.000433 AC: 66 AN: 152260 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00558

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000727 AC: 178 AN: 244692 Hom.: 3 AF XY: 0.000919 AC XY: 122 AN XY: 132740

Gnomad AFR exome AF: 0.0000645

Gnomad AMR exome AF: 0.000264

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00356

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000534

Gnomad OTH exome AF: 0.000502

GnomAD4 exome AF: 0.000512 AC: 746 AN: 1457896 Hom.: 6 Cov.: 32 AF XY: 0.000668 AC XY: 484 AN XY: 724974

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.000270

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00467

Gnomad4 FIN exome AF: 0.0000189

Gnomad4 NFE exome AF: 0.000244

Gnomad4 OTH exome AF: 0.000631

GnomAD4 genome AF: 0.000440 AC: 67 AN: 152378 Hom.: 3 Cov.: 33 AF XY: 0.000577 AC XY: 43 AN XY: 74516

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00600

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000376 Hom.: 0

Bravo AF: 0.000310

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jun 18, 2015

- -

Saldino-Mainzer syndrome Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.74
Dann	Benign	0.43

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: rs144879630; hg19: chr16-1560943;