Genetic Variant TTLL11:p.Arg695Gly (chr9-121822637-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001139442.2(TTLL11):c.2083C>G(p.Arg695Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000398 in 1,506,696 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R695H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000037 ( 0 hom. )

Consequence

TTLL11
NM_001139442.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.430

Publications

1 publications found

Variant links:

Genes affected

TTLL11 (HGNC:18113): (tubulin tyrosine ligase like 11) Predicted to enable tubulin binding activity and tubulin-glutamic acid ligase activity. Predicted to be involved in microtubule cytoskeleton organization and protein polyglutamylation. Predicted to act upstream of or within microtubule severing. Predicted to be located in cytosol. Predicted to be active in cilium. [provided by Alliance of Genome Resources, Apr 2022]

TTLL11 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05241558).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTLL11	NM_001139442.2 link	c.2083C>G	p.Arg695Gly	missense_variant	Exon 9 of 9	ENST00000321582.11	NP_001132914.2	Q8NHH1Q6ZUZ3
TTLL11	NM_001386833.1 link	c.430C>G	p.Arg144Gly	missense_variant	Exon 4 of 4		NP_001373762.1
TTLL11	XM_047422825.1 link	c.1507C>G	p.Arg503Gly	missense_variant	Exon 8 of 8		XP_047278781.1
TTLL11	XR_001746188.2 link	n.2243C>G		non_coding_transcript_exon_variant	Exon 9 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTLL11	ENST00000321582.11 link	c.2083C>G	p.Arg695Gly	missense_variant	Exon 9 of 9	5	NM_001139442.2	ENSP00000321346.6		Q8NHH1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000369

AC:

AN:

1354514

Hom.:

Cov.:

AF XY:

0.00000151

AC XY:

AN XY:

664054

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30130

American (AMR)

AF:

0.00

AC:

AN:

29320

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22010

East Asian (EAS)

AF:

0.00

AC:

AN:

35292

South Asian (SAS)

AF:

0.00

AC:

AN:

71800

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47080

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3918

European-Non Finnish (NFE)

AF:

0.00000472

AC:

AN:

1059072

Other (OTH)

AF:

0.00

AC:

AN:

55892

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74348

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41446

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.84

CADD

Benign

1.9

(source)

DANN

Benign

0.77

DEOGEN2

Benign

0.0075

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.025

LIST_S2

Benign

0.37

M_CAP

Benign

0.026

MetaRNN

Benign

0.052

MetaSVM

Benign

-0.95

PhyloP100

0.43

PrimateAI

Benign

0.22

PROVEAN

Benign

-1.3

REVEL

Benign

0.027

Sift

Benign

0.57

Sift4G

Benign

0.14

Vest4

0.057

MutPred

0.12

Gain of relative solvent accessibility (P = 0.0166);

MVP

0.067

MPC

0.80

ClinPred

0.042

GERP RS

-2.4

Varity_R

0.038

gMVP

0.30

Mutation Taster

=94/6

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over