Genetic Variant TTLL7:p.Gly872Val (chr1-83870011-C-A) – 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.2615G>T(p.Gly872Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,437,194 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. G872A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TTLL7
NM_024686.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.34

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=0.16364878).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTLL7	NM_024686.6 link	c.2615G>T	p.Gly872Val	missense_variant	Exon 21 of 21	ENST00000260505.13	NP_078962.4	Q6ZT98-1
TTLL7	NM_001350214.2 link	c.2615G>T	p.Gly872Val	missense_variant	Exon 22 of 22		NP_001337143.1
TTLL7	NM_001350215.2 link	c.2534G>T	p.Gly845Val	missense_variant	Exon 20 of 20		NP_001337144.1
TTLL7	XM_047430691.1 link	c.1880G>T	p.Gly627Val	missense_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.2615G>T	p.Gly872Val	missense_variant	Exon 21 of 21	2	NM_024686.6	ENSP00000260505.8		Q6ZT98-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000439

AC:

AN:

227826

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000626

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000139

AC:

AN:

1437194

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

714484

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

31990

American (AMR)

AF:

0.00

AC:

AN:

38874

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25682

East Asian (EAS)

AF:

0.0000264

AC:

AN:

37850

South Asian (SAS)

AF:

0.00

AC:

AN:

81362

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53234

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5726

European-Non Finnish (NFE)

AF:

9.07e-7

AC:

AN:

1103066

Other (OTH)

AF:

0.00

AC:

AN:

59410

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.006664), 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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Uncertain

0.016

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.057

Eigen

Benign

0.10

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.80

M_CAP

Benign

0.0046

MetaRNN

Benign

0.16

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.5

PhyloP100

3.3

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.6

REVEL

Benign

0.12

Sift

Uncertain

0.011

Sift4G

Uncertain

0.053

Polyphen

0.15

Vest4

0.42

MutPred

0.23

Loss of disorder (P = 0.0396);

MVP

0.30

MPC

0.82

ClinPred

0.64

GERP RS

4.9

Varity_R

0.29

gMVP

0.58

Mutation Taster

=80/20

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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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1-83870011-C-A

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