5-160051178-T-C

Variant names:

• chr5-160051178-T-C
• rs1413092475
• NM_003314.3:c.740T>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003314.3(TTC1):​c.740T>C​(p.Met247Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,458,016 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TTC1 NM_003314.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.61

Genes affected

TTC1 (HGNC:12391): (tetratricopeptide repeat domain 1) This gene encodes a protein that belongs to the tetratrico peptide repeat superfamily of proteins. The encoded protein plays a role in protein-protein interactions, and binds to the Galpha subunit of G protein-coupled receptors to activate the Ras signaling pathway. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]

PWWP2A (HGNC:29406): (PWWP domain containing 2A) Enables chromatin binding activity and histone binding activity. Located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTC1	NM_003314.3	c.740T>C	p.Met247Thr	missense_variant	Exon 7 of 8	ENST00000231238.10	NP_003305.1
TTC1	NM_001282500.2	c.740T>C	p.Met247Thr	missense_variant	Exon 7 of 8		NP_001269429.1
PWWP2A	XM_011534424.4	c.1567-5919A>G		intron_variant	Intron 3 of 3		XP_011532726.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTC1	ENST00000231238.10	c.740T>C	p.Met247Thr	missense_variant	Exon 7 of 8	1	NM_003314.3	ENSP00000231238.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1458016 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725446

Gnomad4 AFR exome AF: 0.0000300

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.740T>C (p.M247T) alteration is located in exon 7 (coding exon 6) of the TTC1 gene. This alteration results from a T to C substitution at nucleotide position 740, causing the methionine (M) at amino acid position 247 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	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	T;T;T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.95	.;D;D
M_CAP	Benign	0.055	D
MetaRNN	Uncertain	0.65	D;D;D
MetaSVM	Benign	-0.75	T
MutationAssessor	Pathogenic	3.1	M;M;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.5	D;D;D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.73
MutPred		0.39		Loss of catalytic residue at M247 (P = 0.0315);Loss of catalytic residue at M247 (P = 0.0315);.;
MVP		0.66
MPC		0.52
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.80
gMVP		0.76

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

Other links and lift over

dbSNP: rs1413092475; hg19: chr5-159478185;