2-74490427-G-T

Position:

• chr2-74490427-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_022492.6(TTC31):​c.416G>T​(p.Ser139Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: TTC31 NM_022492.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.539

Genes affected

TTC31 (HGNC:25759): (tetratricopeptide repeat domain 31)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1820172).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTC31	NM_022492.6	c.416G>T	p.Ser139Ile	missense_variant	4/13	ENST00000233623.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTC31	ENST00000233623.11	c.416G>T	p.Ser139Ile	missense_variant	4/13	1	NM_022492.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

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

Mar 29, 2023

The c.416G>T (p.S139I) alteration is located in exon 4 (coding exon 4) of the TTC31 gene. This alteration results from a G to T substitution at nucleotide position 416, causing the serine (S) at amino acid position 139 to be replaced by an isoleucine (I). 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	0.13
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0088	.;.;T
Eigen	Benign	0.084
Eigen_PC	Benign	-0.0068
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.73	T;T;T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.0	L;.;L
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.5	.;D;N
REVEL	Benign	0.24
Sift	Uncertain	0.0020	.;D;D
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		0.95	.;.;P
Vest4		0.23
MutPred		0.35		Gain of helix (P = 0.0078);Gain of helix (P = 0.0078);Gain of helix (P = 0.0078);
MVP		0.83
MPC		0.41
ClinPred		0.97	D
GERP RS		1.5
Varity_R		0.23
gMVP		0.14

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: rs140012562; hg19: chr2-74717554;