chr12-110127411-A-C

Position:

• chr12-110127411-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014055.4(IFT81):​c.31A>C​(p.Ser11Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000112 in 1,600,048 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000097 (0 hom.)
• Consequence: IFT81 NM_014055.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.19

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.073170125).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IFT81	NM_014055.4	c.31A>C	p.Ser11Arg	missense_variant	2/19	ENST00000242591.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFT81	ENST00000242591.10	c.31A>C	p.Ser11Arg	missense_variant	2/19	1	NM_014055.4	P1
IFT81	ENST00000552912.5	c.31A>C	p.Ser11Arg	missense_variant	2/19	1		P1
IFT81	ENST00000361948.8	c.31A>C	p.Ser11Arg	missense_variant	2/12	1
IFT81	ENST00000546374.5	c.31A>C	p.Ser11Arg	missense_variant	2/10	5

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152236 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000430 AC: 1 AN: 232750 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 125944

Gnomad AFR exome AF: 0.0000692

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000967 AC: 14 AN: 1447694 Hom.: 0 Cov.: 30 AF XY: 0.0000111 AC XY: 8 AN XY: 719454

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000330

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.04e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152354 Hom.: 0 Cov.: 31 AF XY: 0.0000268 AC XY: 2 AN XY: 74498

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ExAC AF: 0.00000825 AC: 1

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

May 05, 2022

This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 11 of the IFT81 protein (p.Ser11Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with IFT81-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.065	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.0056	.;T;T;.
Eigen	Benign	-0.19
Eigen_PC	Benign	0.079
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.93	D;.;D;D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.073	T;T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	-0.34	N;N;N;.
MutationTaster	Benign	0.97	N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.36	N;N;N;N
REVEL	Benign	0.26
Sift	Benign	0.34	T;T;T;T
Sift4G	Benign	0.061	T;T;T;T
Polyphen		0.082	B;B;B;.
Vest4		0.23
MutPred		0.51		Gain of MoRF binding (P = 0.0145);Gain of MoRF binding (P = 0.0145);Gain of MoRF binding (P = 0.0145);Gain of MoRF binding (P = 0.0145);
MVP		0.75
MPC		0.15
ClinPred		0.22	T
GERP RS		6.2
Varity_R		0.16
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs191678360; hg19: chr12-110565216;