rs776524418

Variant names:

• chr12-110127431-T-A
• rs776524418
• NM_014055.4:c.51T>A

Your query was ambiguous. Multiple possible variants found:

• chr12-110127431-T-A
• chr12-110127431-T-C

Variant summary

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

The NM_014055.4(IFT81):​c.51T>A​(p.Phe17Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,188 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. F17F) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
• Consequence: IFT81 NM_014055.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.85
• 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, 0.751

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.51T>A	p.Phe17Leu	missense	Exon 2 of 19	NP_054774.2
	IFT81	NM_001143779.2		c.51T>A	p.Phe17Leu	missense	Exon 2 of 19	NP_001137251.1	Q8WYA0-1
	IFT81	NM_001347946.2		c.51T>A	p.Phe17Leu	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.51T>A	p.Phe17Leu	missense	Exon 2 of 19	ENSP00000242591.5	Q8WYA0-1
	IFT81	ENST00000552912.5	TSL:1	c.51T>A	p.Phe17Leu	missense	Exon 2 of 19	ENSP00000449718.1	Q8WYA0-1
	IFT81	ENST00000361948.8	TSL:1	c.51T>A	p.Phe17Leu	missense	Exon 2 of 12	ENSP00000355372.4	Q8WYA0-3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152188 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152188 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74340

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.060	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Uncertain	-0.081	T
MutationAssessor	Benign	2.0	M
PhyloP100		1.9
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.63
Sift	Benign	0.19	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.80
MutPred		0.65		Gain of helix (P = 0.062)
MVP		0.84
MPC		0.48
ClinPred		0.96	D
GERP RS		6.1
Varity_R		0.44
gMVP		0.71
Mutation Taster		=17/83	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs776524418; hg19: chr12-110565236;