12-110127382-T-A

Position:

• chr12-110127382-T-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_014055.4(IFT81):​c.2T>A​(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000704 in 1,420,664 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: IFT81 NM_014055.4 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.67

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IFT81	NM_014055.4	c.2T>A	p.Met1?	start_lost	2/19	ENST00000242591.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFT81	ENST00000242591.10	c.2T>A	p.Met1?	start_lost	2/19	1	NM_014055.4	P1
IFT81	ENST00000552912.5	c.2T>A	p.Met1?	start_lost	2/19	1		P1
IFT81	ENST00000361948.8	c.2T>A	p.Met1?	start_lost	2/12	1
IFT81	ENST00000546374.5	c.2T>A	p.Met1?	start_lost	2/10	5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.04e-7 AC: 1 AN: 1420664 Hom.: 0 Cov.: 30 AF XY: 0.00000142 AC XY: 1 AN XY: 705238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.12e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 21, 2022

This variant is not present in population databases (gnomAD no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has not been reported in the literature in individuals affected with IFT81-related conditions. This sequence change affects the initiator methionine of the IFT81 mRNA. The next in-frame methionine is located at codon 9. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	.;T;T;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;.;D;D
M_CAP	Uncertain	0.090	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Benign	-0.48	T
MutationTaster	Benign	1.0	D;D;D
PROVEAN	Pathogenic	-4.5	D;D;D;D
REVEL	Uncertain	0.57
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		0.98	D;D;D;.
Vest4		0.93
MutPred		0.87		Gain of ubiquitination at M1 (P = 0.0325);Gain of ubiquitination at M1 (P = 0.0325);Gain of ubiquitination at M1 (P = 0.0325);Gain of ubiquitination at M1 (P = 0.0325);
MVP		0.77
ClinPred		0.99	D
GERP RS		6.2
Varity_R		0.85
gMVP		0.77

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-110565187;