7-139139909-A-T

Variant names:

• chr7-139139909-A-T
• rs139762669
• NM_024926.4:c.254A>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_024926.4(IFT56):​c.254A>T​(p.Lys85Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000931 in 1,611,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: IFT56 NM_024926.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.53
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33501944).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IFT56	NM_024926.4	c.254A>T	p.Lys85Ile	missense_variant	Exon 4 of 18	ENST00000464848.5	NP_079202.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IFT56	ENST00000464848.5	c.254A>T	p.Lys85Ile	missense_variant	Exon 4 of 18	1	NM_024926.4	ENSP00000419279.1
IFT56	ENST00000478836.6	c.254A>T	p.Lys85Ile	missense_variant	Exon 4 of 16	2		ENSP00000419178.2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152170 Hom.: 0 Cov.: 32

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: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.00000822 AC: 12 AN: 1459640 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 726096

African (AFR) AF: 0.00 AC: 0 AN: 33386

American (AMR) AF: 0.00 AC: 0 AN: 44310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26058

East Asian (EAS) AF: 0.00 AC: 0 AN: 39550

South Asian (SAS) AF: 0.00 AC: 0 AN: 85716

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53332

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00000990 AC: 11 AN: 1111224

Other (OTH) AF: 0.00 AC: 0 AN: 60308

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152170 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74334

African (AFR) AF: 0.00 AC: 0 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68026

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 08, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.254A>T (p.K85I) alteration is located in exon 4 (coding exon 4) of the TTC26 gene. This alteration results from a A to T substitution at nucleotide position 254, causing the lysine (K) at amino acid position 85 to be replaced by an isoleucine (I). 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	0.22
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.65	.;D;D;D;D;.
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.87	D;D;D;D;D;T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.34	T;T;T;T;T;T
MetaSVM	Benign	-0.39	T
PhyloP100		4.5
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-4.6	D;D;D;D;D;D
REVEL	Benign	0.16
Sift	Benign	0.032	D;T;T;D;D;D
Sift4G	Uncertain	0.050	T;T;T;T;T;T
Polyphen		0.0020, 0.57, 0.061, 0.19	.;B;P;B;B;.
Vest4		0.46
MVP		0.72
MPC		0.47
ClinPred		0.91	D
GERP RS		5.5
Varity_R		0.53
gMVP		0.49
Mutation Taster		=74/26	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

dbSNP: rs139762669; hg19: chr7-138824655;