rs61745103

Positions:

• chr16-1519931-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_014714.4(IFT140):​c.3990G>A​(p.Ala1330=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00538 in 1,600,638 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (12 hom., cov: 33)
  • Exomes 𝑓: 0.0048 (41 hom.)
• Consequence: IFT140 NM_014714.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -5.37

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=-0.85).
• BP6: Variant 16-1519931-C-T is Benign according to our data. Variant chr16-1519931-C-T is described in ClinVar as [Benign]. Clinvar id is 317993.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.37 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0108 (1650/152388) while in subpopulation AFR AF= 0.028 (1166/41592). AF 95% confidence interval is 0.0267. There are 12 homozygotes in gnomad4. There are 771 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IFT140	NM_014714.4	c.3990G>A	p.Ala1330=	synonymous_variant	29/31	ENST00000426508.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFT140	ENST00000426508.7	c.3990G>A	p.Ala1330=	synonymous_variant	29/31	5	NM_014714.4	P1

Frequencies

GnomAD3 genomes AF: 0.0108 AC: 1647 AN: 152270 Hom.: 13 Cov.: 33

Gnomad AFR AF: 0.0280

Gnomad AMI AF: 0.0242

Gnomad AMR AF: 0.00490

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.00868

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00454

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.00535 AC: 1279 AN: 239078 Hom.: 8 AF XY: 0.00525 AC XY: 681 AN XY: 129674

Gnomad AFR exome AF: 0.0288

Gnomad AMR exome AF: 0.00235

Gnomad ASJ exome AF: 0.000875

Gnomad EAS exome AF: 0.000228

Gnomad SAS exome AF: 0.00835

Gnomad FIN exome AF: 0.000287

Gnomad NFE exome AF: 0.00423

Gnomad OTH exome AF: 0.00435

GnomAD4 exome AF: 0.00481 AC: 6965 AN: 1448250 Hom.: 41 Cov.: 32 AF XY: 0.00493 AC XY: 3553 AN XY: 720164

Gnomad4 AFR exome AF: 0.0288

Gnomad4 AMR exome AF: 0.00243

Gnomad4 ASJ exome AF: 0.000554

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.00899

Gnomad4 FIN exome AF: 0.000665

Gnomad4 NFE exome AF: 0.00432

Gnomad4 OTH exome AF: 0.00499

GnomAD4 genome AF: 0.0108 AC: 1650 AN: 152388 Hom.: 12 Cov.: 33 AF XY: 0.0103 AC XY: 771 AN XY: 74526

Gnomad4 AFR AF: 0.0280

Gnomad4 AMR AF: 0.00490

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.00890

Gnomad4 FIN AF: 0.000753

Gnomad4 NFE AF: 0.00453

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.00737 Hom.: 4

Bravo AF: 0.0117

Asia WGS AF: 0.00462 AC: 16 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 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

Saldino-Mainzer syndrome;C4540439:Retinitis pigmentosa 80 Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 20, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.13
DANN	Benign	0.54

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: rs61745103; hg19: chr16-1569932;