12-110127523-A-T

Position:

• chr12-110127523-A-T

Variant summary

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

The NM_014055.4(IFT81):​c.143A>T​(p.Lys48Met) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: IFT81 NM_014055.4 missense, splice_region
• Scores: Splicing: ADA: 0.5445
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.15

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 2 ACMG points.

• 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.143A>T	p.Lys48Met	missense_variant, splice_region_variant	2/19	ENST00000242591.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFT81	ENST00000242591.10	c.143A>T	p.Lys48Met	missense_variant, splice_region_variant	2/19	1	NM_014055.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 14, 2022

The c.143A>T (p.K48M) alteration is located in exon 2 (coding exon 1) of the IFT81 gene. This alteration results from a A to T substitution at nucleotide position 143, causing the lysine (K) at amino acid position 48 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	.;T;T;.
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;.;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.58	D;D;D;D
MetaSVM	Uncertain	0.15	D
MutationAssessor	Uncertain	2.6	M;M;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.7	D;D;D;D
REVEL	Uncertain	0.57
Sift	Uncertain	0.025	D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.56
MutPred		0.34		Gain of catalytic residue at L50 (P = 2e-04);Gain of catalytic residue at L50 (P = 2e-04);Gain of catalytic residue at L50 (P = 2e-04);Gain of catalytic residue at L50 (P = 2e-04);
MVP		0.92
MPC		0.61
ClinPred		0.98	D
GERP RS		5.0
Varity_R		0.33
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.54
dbscSNV1_RF	Benign	0.59
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-110565328;