17-18798884-C-T

Position:

• chr17-18798884-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_016078.6(TVP23B):​c.403C>T​(p.Pro135Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,660 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: 30)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TVP23B NM_016078.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.32

Genes affected

TVP23B (HGNC:20399): (trans-golgi network vesicle protein 23 homolog B) Predicted to be involved in protein secretion and vesicle-mediated transport. Predicted to be integral component of membrane. Predicted to be integral component of Golgi membrane. [provided by Alliance of Genome Resources, Apr 2022]

TVP23B (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.899

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TVP23B	NM_016078.6	c.403C>T	p.Pro135Ser	missense_variant	5/7	ENST00000307767.13	NP_057162.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TVP23B	ENST00000307767.13	c.403C>T	p.Pro135Ser	missense_variant	5/7	1	NM_016078.6	ENSP00000305654.8

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461660 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727136

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

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

Jul 26, 2022

The c.403C>T (p.P135S) alteration is located in exon 5 (coding exon 5) of the TVP23B gene. This alteration results from a C to T substitution at nucleotide position 403, causing the proline (P) at amino acid position 135 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	0.33
BayesDel_addAF	Benign	-0.071	T
BayesDel_noAF	Benign	-0.34
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T;T;T;T;T
Eigen	Benign	0.098
Eigen_PC	Benign	-0.038
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.77	T;T;T;.;T
M_CAP	Benign	0.033	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D
MetaSVM	Benign	-0.72	T
MutationAssessor	Pathogenic	3.0	M;.;.;.;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-6.1	D;.;.;.;.
REVEL	Benign	0.26
Sift	Benign	0.045	D;.;.;.;.
Sift4G	Uncertain	0.039	D;D;D;D;D
Polyphen		0.93	P;.;.;.;.
Vest4		0.83
MutPred		0.80		Gain of MoRF binding (P = 0.223);Gain of MoRF binding (P = 0.223);.;.;.;
MVP		0.27
MPC		1.4
ClinPred		0.99	D
GERP RS		2.1
Varity_R		0.52
gMVP		0.80

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-18702197;