20-31922980-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001008409.5(TTLL9):​c.591C>A​(p.Asp197Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000992 in 1,613,598 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. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

TTLL9
NM_001008409.5 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.34
Variant links:
Genes affected
TTLL9 (HGNC:16118): (tubulin tyrosine ligase like 9) 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 flagellated sperm motility. Predicted to be located in ciliary basal body; cytoplasm; and microtubule. Predicted to be active in cilium. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.03454581).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TTLL9NM_001008409.5 linkc.591C>A p.Asp197Glu missense_variant Exon 8 of 15 ENST00000535842.6 NP_001008409.1 Q3SXZ7-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TTLL9ENST00000535842.6 linkc.591C>A p.Asp197Glu missense_variant Exon 8 of 15 5 NM_001008409.5 ENSP00000442515.1 Q3SXZ7-1

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152202
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.000288
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:
0.00
GnomAD3 exomes
AF:
0.0000321
AC:
8
AN:
249506
Hom.:
0
AF XY:
0.0000295
AC XY:
4
AN XY:
135368
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000174
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000177
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000753
AC:
11
AN:
1461396
Hom.:
0
Cov.:
30
AF XY:
0.00000688
AC XY:
5
AN XY:
727040
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000157
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000329
AC:
5
AN:
152202
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74372
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.000288
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000340
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Apr 22, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.591C>A (p.D197E) alteration is located in exon 8 (coding exon 7) of the TTLL9 gene. This alteration results from a C to A substitution at nucleotide position 591, causing the aspartic acid (D) at amino acid position 197 to be replaced by a glutamic acid (E). 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
0.081
BayesDel_addAF
Benign
-0.62
T
BayesDel_noAF
Benign
-0.86
CADD
Benign
0.035
DANN
Benign
0.72
DEOGEN2
Benign
0.0048
T;T;.
Eigen
Benign
-1.7
Eigen_PC
Benign
-1.6
FATHMM_MKL
Benign
0.070
N
LIST_S2
Benign
0.52
.;T;T
M_CAP
Benign
0.0014
T
MetaRNN
Benign
0.035
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
-0.36
N;N;.
PrimateAI
Benign
0.39
T
PROVEAN
Benign
-0.26
N;N;.
REVEL
Benign
0.044
Sift
Benign
0.64
T;T;.
Sift4G
Benign
0.74
T;T;T
Polyphen
0.0030
B;B;.
Vest4
0.099
MutPred
0.30
Loss of stability (P = 0.1522);Loss of stability (P = 0.1522);.;
MVP
0.014
MPC
0.11
ClinPred
0.029
T
GERP RS
-4.0
Varity_R
0.033
gMVP
0.16

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs749750682; hg19: chr20-30510783; API