14-20295370-C-T

Position:

• chr14-20295370-C-T

Variant summary

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

The NM_138376.3(TTC5):​c.1000G>A​(p.Gly334Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: TTC5 NM_138376.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.63

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]

TTC5 (HGNC:):

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/exons	MANE	Protein	UniProt
TTC5	NM_138376.3	c.1000G>A	p.Gly334Ser	missense_variant	8/10	ENST00000258821.8	NP_612385.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTC5	ENST00000258821.8	c.1000G>A	p.Gly334Ser	missense_variant	8/10	1	NM_138376.3	ENSP00000258821.3
TTC5	ENST00000383029.7	n.*545G>A		non_coding_transcript_exon_variant	8/10	1		ENSP00000372496.3
TTC5	ENST00000383029.7	n.*545G>A		3_prime_UTR_variant	8/10	1		ENSP00000372496.3
TTC5	ENST00000554157.5	n.1011G>A		non_coding_transcript_exon_variant	8/9	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461892 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 727246

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

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 26, 2022

The c.1000G>A (p.G334S) alteration is located in exon 8 (coding exon 8) of the TTC5 gene. This alteration results from a G to A substitution at nucleotide position 1000, causing the glycine (G) at amino acid position 334 to be replaced by a serine (S). 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	0.11
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.053	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.018	T
MetaRNN	Uncertain	0.67	D
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	1.5	L
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.12
Sift	Benign	0.37	T
Sift4G	Benign	0.62	T
Polyphen		0.97	D
Vest4		0.63
MutPred		0.57		Loss of glycosylation at S333 (P = 0.0604);
MVP		0.46
MPC		0.48
ClinPred		0.89	D
GERP RS		5.5
Varity_R		0.22
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1882038520; hg19: chr14-20763529;