14-20296391-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_138376.3(TTC5):​c.695C>T​(p.Thr232Met) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000422 in 1,611,756 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000032 ( 2 hom. )

Consequence

TTC5
NM_138376.3 missense, splice_region

Scores

1
8
10
Splicing: ADA: 0.9915
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.32
Variant links:
Genes affected
TTC5 (HGNC:19274): (tetratricopeptide repeat domain 5) Predicted to enable DNA binding activity and chromatin binding activity. Predicted to be involved in DNA repair. Predicted to act upstream of or within positive regulation of transcription by RNA polymerase II. Located in nucleoplasm. [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 -4 ACMG points.

BS2
High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TTC5NM_138376.3 linkc.695C>T p.Thr232Met missense_variant, splice_region_variant 6/10 ENST00000258821.8 NP_612385.2 Q8N0Z6Q86T04

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TTC5ENST00000258821.8 linkc.695C>T p.Thr232Met missense_variant, splice_region_variant 6/101 NM_138376.3 ENSP00000258821.3 Q8N0Z6
TTC5ENST00000383029.7 linkn.*240C>T splice_region_variant, non_coding_transcript_exon_variant 6/101 ENSP00000372496.3 H9KV81
TTC5ENST00000383029.7 linkn.*240C>T 3_prime_UTR_variant 6/101 ENSP00000372496.3 H9KV81
TTC5ENST00000554157.5 linkn.706C>T splice_region_variant, non_coding_transcript_exon_variant 6/92

Frequencies

GnomAD3 genomes
AF:
0.000138
AC:
21
AN:
152112
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000557
AC:
14
AN:
251426
Hom.:
0
AF XY:
0.0000515
AC XY:
7
AN XY:
135878
show subpopulations
Gnomad AFR exome
AF:
0.000369
Gnomad AMR exome
AF:
0.000116
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000980
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000879
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000322
AC:
47
AN:
1459526
Hom.:
2
Cov.:
28
AF XY:
0.0000372
AC XY:
27
AN XY:
726290
show subpopulations
Gnomad4 AFR exome
AF:
0.000329
Gnomad4 AMR exome
AF:
0.0000895
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000928
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.00000721
Gnomad4 OTH exome
AF:
0.000149
GnomAD4 genome
AF:
0.000138
AC:
21
AN:
152230
Hom.:
0
Cov.:
33
AF XY:
0.000107
AC XY:
8
AN XY:
74434
show subpopulations
Gnomad4 AFR
AF:
0.000482
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.000288
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000263
Hom.:
0
Bravo
AF:
0.000200
ESP6500AA
AF:
0.000681
AC:
3
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000824
AC:
10

ClinVar

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

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJan 25, 2022In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously reported as a pathogenic or benign germline variant to our knowledge; This variant is associated with the following publications: (PMID: 22996961) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Benign
-0.0071
T
BayesDel_noAF
Uncertain
0.080
CADD
Pathogenic
31
DANN
Uncertain
1.0
DEOGEN2
Benign
0.22
T
Eigen
Uncertain
0.49
Eigen_PC
Uncertain
0.56
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.91
D
M_CAP
Benign
0.030
D
MetaRNN
Benign
0.19
T
MetaSVM
Benign
-0.53
T
MutationAssessor
Uncertain
2.0
M
PrimateAI
Uncertain
0.65
T
PROVEAN
Benign
-1.8
N
REVEL
Uncertain
0.45
Sift
Benign
0.25
T
Sift4G
Benign
0.32
T
Polyphen
0.94
P
Vest4
0.64
MVP
0.79
MPC
0.51
ClinPred
0.10
T
GERP RS
5.1
Varity_R
0.18
gMVP
0.43

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
0.99
dbscSNV1_RF
Pathogenic
0.79
SpliceAI score (max)
0.060
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: rs150011121; hg19: chr14-20764550; COSMIC: COSV51871139; COSMIC: COSV51871139; API