12-110127467-G-C

Variant names:

• chr12-110127467-G-C
• rs751222088
• NM_014055.4:c.87G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PP5_Very_Strong

The NM_014055.4(IFT81):​c.87G>C​(p.Leu29Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000137 in 1,610,172 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: IFT81 NM_014055.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 1.16
• Publications: 1 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, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
• ciliopathy

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PP5: Variant 12-110127467-G-C is Pathogenic according to our data. Variant chr12-110127467-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 495122.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFT81	NM_014055.4	MANE Select	c.87G>C	p.Leu29Phe	missense	Exon 2 of 19	NP_054774.2
	IFT81	NM_001143779.2		c.87G>C	p.Leu29Phe	missense	Exon 2 of 19	NP_001137251.1	Q8WYA0-1
	IFT81	NM_001347946.2		c.87G>C	p.Leu29Phe	missense	Exon 2 of 12	NP_001334875.1	Q8WYA0-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFT81	ENST00000242591.10	TSL:1 MANE Select	c.87G>C	p.Leu29Phe	missense	Exon 2 of 19	ENSP00000242591.5	Q8WYA0-1
	IFT81	ENST00000552912.5	TSL:1	c.87G>C	p.Leu29Phe	missense	Exon 2 of 19	ENSP00000449718.1	Q8WYA0-1
	IFT81	ENST00000361948.8	TSL:1	c.87G>C	p.Leu29Phe	missense	Exon 2 of 12	ENSP00000355372.4	Q8WYA0-3

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152090 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000724

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000366 AC: 9 AN: 245732 AF XY: 0.0000376

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000808

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000148 AC: 216 AN: 1458082 Hom.: 0 Cov.: 30 AF XY: 0.000163 AC XY: 118 AN XY: 725172

African (AFR) AF: 0.00 AC: 0 AN: 33326

American (AMR) AF: 0.00 AC: 0 AN: 44124

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25832

East Asian (EAS) AF: 0.00 AC: 0 AN: 39550

South Asian (SAS) AF: 0.00 AC: 0 AN: 85520

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53308

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.000193 AC: 214 AN: 1110438

Other (OTH) AF: 0.0000332 AC: 2 AN: 60224

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152090 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74310

African (AFR) AF: 0.0000724 AC: 3 AN: 41412

American (AMR) AF: 0.00 AC: 0 AN: 15270

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: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2080

Alfa AF: 0.0000565 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.0000412 AC: 5

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.58	D
MetaSVM	Uncertain	0.33	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		1.2
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.61
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.018	D
Polyphen		1.0	D
Vest4		0.76
MutPred		0.38		Gain of catalytic residue at D27 (P = 5e-04)
MVP		0.91
MPC		0.61
ClinPred		0.67	D
GERP RS		5.2
Varity_R		0.32
gMVP		0.64
Mutation Taster		=6/94	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

Other links and lift over

dbSNP: rs751222088; hg19: chr12-110565272;