rs61739554

Positions:

• chr16-1592499-C-A
• chr16-1592499-C-T

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.459G>T​(p.Thr153=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00366 in 1,614,194 control chromosomes in the GnomAD database, including 182 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (89 hom., cov: 33)
  • Exomes 𝑓: 0.0021 (93 hom.)
• Consequence: IFT140 NM_014714.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.44

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 16-1592499-C-A is Benign according to our data. Variant chr16-1592499-C-A is described in ClinVar as [Benign]. Clinvar id is 318213.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.44 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.062 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IFT140	NM_014714.4	c.459G>T	p.Thr153=	synonymous_variant	5/31	ENST00000426508.7	NP_055529.2
LOC105371046	NR_135176.1	n.59+11914C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IFT140	ENST00000426508.7	c.459G>T	p.Thr153=	synonymous_variant	5/31	5	NM_014714.4	ENSP00000406012	P1
	ENST00000563162.1	n.59+11914C>A		intron_variant, non_coding_transcript_variant		2
IFT140	ENST00000439987.6	n.520G>T		non_coding_transcript_exon_variant	4/19	2
IFT140	ENST00000397417.6	c.329-8079G>T		intron_variant, NMD_transcript_variant		5		ENSP00000380562

Frequencies

GnomAD3 genomes AF: 0.0187 AC: 2848 AN: 152206 Hom.: 89 Cov.: 33

Gnomad AFR AF: 0.0643

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00818

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: 0.000397

Gnomad OTH AF: 0.0139

GnomAD3 exomes AF: 0.00521 AC: 1309 AN: 251364 Hom.: 44 AF XY: 0.00383 AC XY: 520 AN XY: 135872

Gnomad AFR exome AF: 0.0669

Gnomad AMR exome AF: 0.00428

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.000324

Gnomad NFE exome AF: 0.000352

Gnomad OTH exome AF: 0.00408

GnomAD4 exome AF: 0.00210 AC: 3063 AN: 1461870 Hom.: 93 Cov.: 33 AF XY: 0.00175 AC XY: 1273 AN XY: 727234

Gnomad4 AFR exome AF: 0.0677

Gnomad4 AMR exome AF: 0.00454

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.000356

Gnomad4 NFE exome AF: 0.000254

Gnomad4 OTH exome AF: 0.00442

GnomAD4 genome AF: 0.0187 AC: 2846 AN: 152324 Hom.: 89 Cov.: 33 AF XY: 0.0182 AC XY: 1352 AN XY: 74480

Gnomad4 AFR AF: 0.0641

Gnomad4 AMR AF: 0.00817

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.00526 Hom.: 8

Bravo AF: 0.0216

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000178

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	-0.72
CADD	Benign	0.34
DANN	Benign	0.87

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: rs61739554; hg19: chr16-1642500;