dbSNP rs1653204235: TTLL7:p.Tyr849Cys (chr1-83870080-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_024686.6(TTLL7):c.2546A>G(p.Tyr849Cys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000718 in 1,392,012 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

TTLL7
NM_024686.6 missense, splice_region

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.71

Publications

0 publications found

Variant links:

Genes affected

TTLL7 (HGNC:26242): (tubulin tyrosine ligase like 7) Enables alpha-tubulin binding activity; beta-tubulin binding activity; and tubulin-glutamic acid ligase activity. Involved in protein polyglutamylation. Predicted to be located in 9+0 non-motile cilium and ciliary basal body. Predicted to be active in cilium. [provided by Alliance of Genome Resources, Apr 2022]

TTLL7 links:

ENSG00000303457 (HGNC:):

ENSG00000303457 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.16146639).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTLL7	NM_024686.6 link	c.2546A>G	p.Tyr849Cys	missense_variant, splice_region_variant	Exon 21 of 21	ENST00000260505.13	NP_078962.4	Q6ZT98-1
TTLL7	NM_001350214.2 link	c.2546A>G	p.Tyr849Cys	missense_variant, splice_region_variant	Exon 22 of 22		NP_001337143.1
TTLL7	NM_001350215.2 link	c.2465A>G	p.Tyr822Cys	missense_variant, splice_region_variant	Exon 20 of 20		NP_001337144.1
TTLL7	XM_047430691.1 link	c.1811A>G	p.Tyr604Cys	missense_variant, splice_region_variant	Exon 15 of 15		XP_047286647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTLL7	ENST00000260505.13 link	c.2546A>G	p.Tyr849Cys	missense_variant, splice_region_variant	Exon 21 of 21	2	NM_024686.6	ENSP00000260505.8		Q6ZT98-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.18e-7

AC:

AN:

1392012

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

690546

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29150

American (AMR)

AF:

0.00

AC:

AN:

26794

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23940

East Asian (EAS)

AF:

0.00

AC:

AN:

35876

South Asian (SAS)

AF:

0.00

AC:

AN:

73530

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52772

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5592

European-Non Finnish (NFE)

AF:

9.20e-7

AC:

AN:

1086838

Other (OTH)

AF:

0.00

AC:

AN:

57520

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000468

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 17, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2546A>G (p.Y849C) alteration is located in exon 21 (coding exon 20) of the TTLL7 gene. This alteration results from a A to G substitution at nucleotide position 2546, causing the tyrosine (Y) at amino acid position 849 to be replaced by a cysteine (C). 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

0.16

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.072

Eigen

Benign

-0.11

Eigen_PC

Benign

0.079

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.79

M_CAP

Benign

0.0064

MetaRNN

Benign

0.16

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.5

PhyloP100

1.7

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-1.7

REVEL

Benign

0.072

Sift

Benign

0.11

Sift4G

Benign

0.17

Polyphen

0.049

Vest4

0.41

MutPred

0.42

Loss of stability (P = 0.1328);

MVP

0.19

MPC

0.68

ClinPred

0.29

GERP RS

5.4

Varity_R

0.17

gMVP

0.52

Mutation Taster

=78/22

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over