rs79494390

chr16-1520261-A-G

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.3743T>C(p.Ile1248Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00354 in 1,614,174 control chromosomes in the GnomAD database, including 115 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (59 hom., cov: 33)
  • Exomes 𝑓: 0.0022 (56 hom.)
• Consequence: IFT140 NM_014714.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 9.24

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=0.008605152).
• BP6: Variant 16-1520261-A-G is Benign according to our data. Variant chr16-1520261-A-G is described in ClinVar as [Benign]. Clinvar id is 317998.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1520261-A-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0509 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IFT140	NM_014714.4	c.3743T>C	p.Ile1248Thr	missense_variant	28/31	ENST00000426508.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFT140	ENST00000426508.7	c.3743T>C	p.Ile1248Thr	missense_variant	28/31	5	NM_014714.4	P1
IFT140	ENST00000361339.9	c.1325T>C	p.Ile442Thr	missense_variant	10/13	1
IFT140	ENST00000565298.5	n.3567T>C		non_coding_transcript_exon_variant	16/19	2
IFT140	ENST00000397417.6	c.*2181T>C		3_prime_UTR_variant, NMD_transcript_variant	21/24	5

Frequencies

GnomAD3 genomes AF: 0.0159 AC: 2423 AN: 152170 Hom.: 59 Cov.: 33

Gnomad AFR AF: 0.0524

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00837

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000632

Gnomad OTH AF: 0.0153

GnomAD3 exomes AF: 0.00483 AC: 1215 AN: 251490 Hom.: 21 AF XY: 0.00383 AC XY: 521 AN XY: 135922

Gnomad AFR exome AF: 0.0543

Gnomad AMR exome AF: 0.00309

Gnomad ASJ exome AF: 0.00496

Gnomad EAS exome AF: 0.000217

Gnomad SAS exome AF: 0.00255

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000624

Gnomad OTH exome AF: 0.00358

GnomAD4 exome AF: 0.00224 AC: 3272 AN: 1461886 Hom.: 56 Cov.: 32 AF XY: 0.00209 AC XY: 1523 AN XY: 727242

Gnomad4 AFR exome AF: 0.0553

Gnomad4 AMR exome AF: 0.00420

Gnomad4 ASJ exome AF: 0.00551

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00283

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000402

Gnomad4 OTH exome AF: 0.00532

GnomAD4 genome AF: 0.0160 AC: 2442 AN: 152288 Hom.: 59 Cov.: 33 AF XY: 0.0155 AC XY: 1153 AN XY: 74470

Gnomad4 AFR AF: 0.0527

Gnomad4 AMR AF: 0.00836

Gnomad4 ASJ AF: 0.00605

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.00393

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000632

Gnomad4 OTH AF: 0.0151

Alfa AF: 0.00720 Hom.: 12

Bravo AF: 0.0185

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0491 AC: 216

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.00567 AC: 688

Asia WGS AF: 0.00953 AC: 33 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000771

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 09, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.22
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D
MetaRNN	Benign	0.0086	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-4.1	D;D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		0.97	.;D
Vest4		0.84
MVP		0.74
MPC		0.32
ClinPred		0.033	T
GERP RS		6.0
Varity_R		0.39
gMVP		0.52

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: rs79494390; hg19: chr16-1570262;