17-18804138-G-C

Variant names:

• chr17-18804138-G-C
• rs201426240
• NM_016078.6:c.463G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_016078.6(TVP23B):​c.463G>C​(p.Ala155Pro) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000411 in 1,461,554 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A155S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: TVP23B NM_016078.6 missense, splice_region
• Scores: Splicing: ADA: 0.3124
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.01
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29167438).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016078.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TVP23B	NM_016078.6	MANE Select	c.463G>C	p.Ala155Pro	missense splice_region	Exon 6 of 7	NP_057162.4	Q9NYZ1
	TVP23B	NM_001316919.1		c.271G>C	p.Ala91Pro	missense splice_region	Exon 6 of 7	NP_001303848.1	J3QL63
	TVP23B	NM_001316920.1		c.271G>C	p.Ala91Pro	missense splice_region	Exon 6 of 7	NP_001303849.1	Q9NYZ1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TVP23B	ENST00000307767.13	TSL:1 MANE Select	c.463G>C	p.Ala155Pro	missense splice_region	Exon 6 of 7	ENSP00000305654.8	Q9NYZ1
	TVP23B	ENST00000574226.5	TSL:1	c.463G>C	p.Ala155Pro	missense splice_region	Exon 6 of 6	ENSP00000462334.1	J3KS67
	TVP23B	ENST00000476139.5	TSL:1	c.271G>C	p.Ala91Pro	missense splice_region	Exon 6 of 7	ENSP00000463400.2	J3QL63

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461554 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4 AN XY: 727076

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111788

Other (OTH) AF: 0.0000166 AC: 1 AN: 60372

GnomAD4 genome Cov.: 25

ExAC AF: 0.00000827 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Benign	0.081	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.0087	T
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L
PhyloP100		5.0
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.097
Sift	Benign	0.15	T
Sift4G	Benign	0.18	T
Polyphen		0.0060	B
Vest4		0.47
MutPred		0.74		Loss of stability (P = 0.0608)
MVP		0.12
MPC		0.78
ClinPred		0.38	T
GERP RS		2.7
Varity_R		0.70
gMVP		0.53
Mutation Taster		=38/62	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.31
dbscSNV1_RF	Benign	0.40
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs201426240; hg19: chr17-18707451;