1-54733666-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_004623.5(TTC4):​c.934C>A​(p.Pro312Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000689 in 1,451,946 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

TTC4
NM_004623.5 missense

Scores

3
10
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.53
Variant links:
Genes affected
TTC4 (HGNC:12394): (tetratricopeptide repeat domain 4) This gene encodes a protein that contains tetratricopeptide (TPR) repeats, which often mediate protein-protein interactions and chaperone activity. The encoded protein interacts with heat shock proteins 70 and 90. Alternative splicing results in multiple transcript variants. Naturally-occuring readthrough transcription occurs from upstream gene MROH (maestro heat-like repeat family member 7) to this gene. [provided by RefSeq, Apr 2014]
MROH7-TTC4 (HGNC:49180): (MROH7-TTC4 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring MROH7 (maestro heat-like repeat family member 7) and TTC4 (tetratricopeptide repeat domain 4) genes. Alternative splicing results in multiple transcript variants, which are candidates for nonsense-mediated mRNA decay (NMD) and are unlikely to produce protein products. [provided by RefSeq, Aug 2013]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.785

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TTC4NM_004623.5 linkc.934C>A p.Pro312Thr missense_variant Exon 8 of 10 ENST00000371281.4 NP_004614.3 O95801

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TTC4ENST00000371281.4 linkc.934C>A p.Pro312Thr missense_variant Exon 8 of 10 1 NM_004623.5 ENSP00000360329.3 O95801
MROH7-TTC4ENST00000414150.6 linkn.*636C>A non_coding_transcript_exon_variant Exon 31 of 33 2 ENSP00000410192.2 A0A0A0MT08
MROH7-TTC4ENST00000414150.6 linkn.*636C>A 3_prime_UTR_variant Exon 31 of 33 2 ENSP00000410192.2 A0A0A0MT08

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD3 exomes
AF:
0.00000407
AC:
1
AN:
245580
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
132970
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000895
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.89e-7
AC:
1
AN:
1451946
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
722238
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.04e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31
ExAC
AF:
0.00000824
AC:
1

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Jan 21, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.934C>A (p.P312T) alteration is located in exon 8 (coding exon 8) of the TTC4 gene. This alteration results from a C to A substitution at nucleotide position 934, causing the proline (P) at amino acid position 312 to be replaced by a threonine (T). 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
Uncertain
0.37
BayesDel_addAF
Uncertain
0.016
T
BayesDel_noAF
Benign
-0.21
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.096
T
Eigen
Uncertain
0.52
Eigen_PC
Uncertain
0.55
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.89
D
M_CAP
Benign
0.024
T
MetaRNN
Pathogenic
0.78
D
MetaSVM
Benign
-1.0
T
MutationAssessor
Uncertain
2.6
M
PrimateAI
Uncertain
0.52
T
PROVEAN
Pathogenic
-5.7
D
REVEL
Benign
0.28
Sift
Uncertain
0.028
D
Sift4G
Uncertain
0.0060
D
Polyphen
0.58
P
Vest4
0.77
MVP
0.84
MPC
0.30
ClinPred
0.96
D
GERP RS
5.0
Varity_R
0.67
gMVP
0.64

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: rs758622427; hg19: chr1-55199339; API