rs200335504

Variant names:

• chr12-110192683-C-T
• rs200335504
• NM_014055.4:c.1534C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_014055.4(IFT81):​c.1534C>T​(p.Arg512*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000754 in 1,578,790 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000076 (0 hom.)
• Consequence: IFT81 NM_014055.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 3.30
• Publications: 4 publications found

Genes affected

IFT81 (HGNC:14313): (intraflagellar transport 81) The protein encoded by this gene, together with IFT74, forms a tubulin-binding module of intraflagellar transport complex B. This module is involved in transport of tubulin within the cilium, and the encoded protein is required for ciliogenesis. Mutations in this gene are a cause of short-rib polydactyly syndromes. [provided by RefSeq, Dec 2016]

IFT81 Gene-Disease associations (from GenCC):

• short-rib thoracic dysplasia 19 with or without polydactyly

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• ciliopathy

  Inheritance: AR Classification: LIMITED Submitted by: Franklin by Genoox

ENSG00000289311 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-110192683-C-T is Pathogenic according to our data. Variant chr12-110192683-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 495121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014055.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFT81	NM_014055.4	MANE Select	c.1534C>T	p.Arg512*	stop_gained	Exon 14 of 19	NP_054774.2
	IFT81	NM_001143779.2		c.1534C>T	p.Arg512*	stop_gained	Exon 14 of 19	NP_001137251.1
	IFT81	NM_001347947.2		c.604C>T	p.Arg202*	stop_gained	Exon 13 of 18	NP_001334876.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFT81	ENST00000242591.10	TSL:1 MANE Select	c.1534C>T	p.Arg512*	stop_gained	Exon 14 of 19	ENSP00000242591.5
	IFT81	ENST00000552912.5	TSL:1	c.1534C>T	p.Arg512*	stop_gained	Exon 14 of 19	ENSP00000449718.1
	IFT81	ENST00000969905.1		c.1582C>T	p.Arg528*	stop_gained	Exon 15 of 20	ENSP00000639964.1

Frequencies

GnomAD3 genomes AF: 0.0000658 AC: 10 AN: 152078 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000259 AC: 6 AN: 232066 AF XY: 0.0000159

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000342

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000469

Gnomad NFE exome AF: 0.0000368

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000764 AC: 109 AN: 1426712 Hom.: 0 Cov.: 25 AF XY: 0.0000606 AC XY: 43 AN XY: 709604

African (AFR) AF: 0.00 AC: 0 AN: 32036

American (AMR) AF: 0.00 AC: 0 AN: 39814

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25616

East Asian (EAS) AF: 0.0000257 AC: 1 AN: 38872

South Asian (SAS) AF: 0.00 AC: 0 AN: 80672

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53200

Middle Eastern (MID) AF: 0.000197 AC: 1 AN: 5084

European-Non Finnish (NFE) AF: 0.0000934 AC: 102 AN: 1092394

Other (OTH) AF: 0.0000678 AC: 4 AN: 59024

GnomAD4 genome AF: 0.0000658 AC: 10 AN: 152078 Hom.: 0 Cov.: 32 AF XY: 0.0000808 AC XY: 6 AN XY: 74274

African (AFR) AF: 0.0000483 AC: 2 AN: 41396

American (AMR) AF: 0.00 AC: 0 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10574

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

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000133 Hom.: 0

Bravo AF: 0.0000718

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000123 AC: 1

ExAC AF: 0.0000166 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Short-rib thoracic dysplasia 19 with or without polydactyly (2)
1	-	-	Jeune thoracic dystrophy (1)
1	-	-	not provided (1)
1	-	-	Retinal dystrophy (1)
1	-	-	SHORT-RIB THORACIC DYSPLASIA 19 WITHOUT POLYDACTYLY (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.90	D
PhyloP100		3.3
Vest4		0.57
GERP RS		3.9
Mutation Taster		=4/196	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs200335504; hg19: chr12-110630488;