12-110127426-C-A

Variant names:

• chr12-110127426-C-A
• rs1387434738
• NM_014055.4:c.46C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_014055.4(IFT81):​c.46C>A​(p.Pro16Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: IFT81 NM_014055.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.57
• Publications: 0 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.822

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.46C>A	p.Pro16Thr	missense	Exon 2 of 19	NP_054774.2
	IFT81	NM_001143779.2		c.46C>A	p.Pro16Thr	missense	Exon 2 of 19	NP_001137251.1	Q8WYA0-1
	IFT81	NM_001347946.2		c.46C>A	p.Pro16Thr	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.46C>A	p.Pro16Thr	missense	Exon 2 of 19	ENSP00000242591.5	Q8WYA0-1
	IFT81	ENST00000552912.5	TSL:1	c.46C>A	p.Pro16Thr	missense	Exon 2 of 19	ENSP00000449718.1	Q8WYA0-1
	IFT81	ENST00000361948.8	TSL:1	c.46C>A	p.Pro16Thr	missense	Exon 2 of 12	ENSP00000355372.4	Q8WYA0-3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	0.36	D
MutationAssessor	Pathogenic	2.9	M
PhyloP100		7.6
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.021	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.57		Gain of helix (P = 0.0078)
MVP		0.94
MPC		0.64
ClinPred		1.0	D
GERP RS		6.1
Varity_R		0.88
gMVP		0.74
Mutation Taster		=21/79	disease causing

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: rs1387434738; hg19: chr12-110565231;