7-139147264-A-G

Variant names:

• chr7-139147264-A-G
• NM_024926.4:c.519A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_024926.4(IFT56):​c.519A>G​(p.Ile173Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: IFT56 NM_024926.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.93
• Publications: 0 publications found

Genes affected

IFT56 (HGNC:21882): (intraflagellar transport 56) Predicted to enable intraciliary transport particle B binding activity. Predicted to be involved in cilium organization; protein localization to cilium; and smoothened signaling pathway. Predicted to act upstream of or within manchette assembly. Predicted to be located in cilium. Predicted to be part of intraciliary transport particle B. Predicted to be active in ciliary basal body and ciliary base. [provided by Alliance of Genome Resources, Apr 2022]

IFT56 Gene-Disease associations (from GenCC):

• biliary, renal, neurologic, and skeletal syndrome

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IFT56	NM_024926.4	c.519A>G	p.Ile173Met	missense_variant	Exon 6 of 18	ENST00000464848.5	NP_079202.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IFT56	ENST00000464848.5	c.519A>G	p.Ile173Met	missense_variant	Exon 6 of 18	1	NM_024926.4	ENSP00000419279.1
IFT56	ENST00000478836.6	c.399+4959A>G		intron_variant	Intron 5 of 15	2		ENSP00000419178.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 21, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.519A>G (p.I173M) alteration is located in exon 6 (coding exon 6) of the TTC26 gene. This alteration results from a A to G substitution at nucleotide position 519, causing the isoleucine (I) at amino acid position 173 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	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	.;T;T;.
Eigen	Benign	-0.018
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.69	D;D;D;D
MetaSVM	Uncertain	-0.053	T
PhyloP100		1.9
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-2.6	D;N;D;D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0030	D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D
Polyphen		0.97, 0.58	.;D;P;.
Vest4		0.71
MutPred		0.43		Gain of disorder (P = 0.106);Gain of disorder (P = 0.106);Gain of disorder (P = 0.106);.;
MVP		0.70
MPC		0.67
ClinPred		0.98	D
GERP RS		-3.6
Varity_R		0.64
gMVP		0.57
Mutation Taster		=63/37	polymorphism

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

hg19: chr7-138832010;