5-160064999-C-G

Position:

• chr5-160064999-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003314.3(TTC1):​c.813C>G​(p.Ile271Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,798 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: TTC1 NM_003314.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.27

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 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=0.05224958).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTC1	NM_003314.3	c.813C>G	p.Ile271Met	missense_variant	8/8	ENST00000231238.10	NP_003305.1
TTC1	NM_001282500.2	c.813C>G	p.Ile271Met	missense_variant	8/8		NP_001269429.1
PWWP2A	XM_011534424.4	c.1550-1326G>C		intron_variant			XP_011532726.1
PWWP2A	XR_007058578.1	n.1612-1326G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTC1	ENST00000231238.10	c.813C>G	p.Ile271Met	missense_variant	8/8	1	NM_003314.3	ENSP00000231238	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461798 Hom.: 0 Cov.: 30 AF XY: 0.0000110 AC XY: 8 AN XY: 727200

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 12, 2024

The c.813C>G (p.I271M) alteration is located in exon 8 (coding exon 7) of the TTC1 gene. This alteration results from a C to G substitution at nucleotide position 813, causing the isoleucine (I) at amino acid position 271 to be replaced by a methionine (M). 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	0.28
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	20
DANN	Benign	0.77
DEOGEN2	Benign	0.031	T;T;T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.91	.;D;D
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.052	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.5	N;N;.
MutationTaster	Benign	0.97	D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	0.59	N;N;N
REVEL	Benign	0.086
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.021	B;B;.
Vest4		0.28
MutPred		0.34		Gain of disorder (P = 0.0355);Gain of disorder (P = 0.0355);.;
MVP		0.33
MPC		0.096
ClinPred		0.17	T
GERP RS		4.6
Varity_R		0.051
gMVP		0.25

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: rs1581135434; hg19: chr5-159492006;