rs387907192

Variant names:

• chr16-1564074-C-T
• rs387907192
• NM_014714.4:c.1990G>A
• IFT140 p.Glu664Lys

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS3 PP3_Moderate PP5_Very_Strong

The NM_014714.4(IFT140):​c.1990G>A​(p.Glu664Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000081 in 1,604,608 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV003272289: Experimental studies have shown that this missense change affects IFT140 function (PMID:22503633).".

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: IFT140 NM_014714.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 7.10
• Publications: 16 publications found

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]

IFT140 Gene-Disease associations (from GenCC):

• autosomal dominant polycystic kidney disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics, ClinGen
• IFT140-related recessive ciliopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, Illumina
• short-rib thoracic dysplasia 9 with or without polydactyly

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• retinitis pigmentosa 80

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Leber congenital amaurosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Jeune syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV003272289: Experimental studies have shown that this missense change affects IFT140 function (PMID: 22503633).
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.888
• PP5: Variant 16-1564074-C-T is Pathogenic according to our data. Variant chr16-1564074-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 31679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014714.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFT140	NM_014714.4	MANE Select	c.1990G>A	p.Glu664Lys	missense	Exon 17 of 31	NP_055529.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFT140	ENST00000426508.7	TSL:5 MANE Select	c.1990G>A	p.Glu664Lys	missense	Exon 17 of 31	ENSP00000406012.2	Q96RY7-1
	IFT140	ENST00000889170.1		c.1990G>A	p.Glu664Lys	missense	Exon 16 of 30	ENSP00000559229.1
	IFT140	ENST00000962400.1		c.1990G>A	p.Glu664Lys	missense	Exon 16 of 30	ENSP00000632459.1

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152240 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 250114 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000551 AC: 8 AN: 1452368 Hom.: 0 Cov.: 30 AF XY: 0.00000277 AC XY: 2 AN XY: 720984

African (AFR) AF: 0.0000301 AC: 1 AN: 33232

American (AMR) AF: 0.0000449 AC: 2 AN: 44514

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25978

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39310

South Asian (SAS) AF: 0.00 AC: 0 AN: 85752

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53312

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.00000362 AC: 4 AN: 1104694

Other (OTH) AF: 0.00 AC: 0 AN: 59840

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152240 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74384

African (AFR) AF: 0.0000724 AC: 3 AN: 41464

American (AMR) AF: 0.000131 AC: 2 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68046

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Saldino-Mainzer syndrome (4)
2	-	-	not provided (2)
1	-	-	Retinitis pigmentosa 80 (1)
1	-	-	Saldino-Mainzer syndrome;C4540439:Retinitis pigmentosa 80 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.51	D
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		7.1
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.59
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.013	D
Varity_R		0.47
gMVP		0.86
Mutation Taster		=19/81	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs387907192;

hg19: chr16-1614075;

COSMIC: COSV68487441;