rs10483802

Variant names:

• chr14-67650704-T-C
• rs10483802
• NM_006370.3:c.*681A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006370.3(VTI1B):​c.*681A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0605 in 1,612,962 control chromosomes in the GnomAD database, including 5,092 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.090 (866 hom., cov: 32)
  • Exomes 𝑓: 0.057 (4226 hom.)
• Consequence: VTI1B NM_006370.3 3_prime_UTR
• Scores: Splicing: ADA: 0.00004983
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.82
• Publications: 9 publications found

Genes affected

VTI1B (HGNC:17793): (vesicle transport through interaction with t-SNAREs 1B) Enables SNARE binding activity and chloride channel inhibitor activity. Involved in regulation of protein localization to plasma membrane. Located in several cellular components, including endosome membrane; lysosomal membrane; and perinuclear region of cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ARG2 (HGNC:664): (arginase 2) Arginase catalyzes the hydrolysis of arginine to ornithine and urea. At least two isoforms of mammalian arginase exists (types I and II) which differ in their tissue distribution, subcellular localization, immunologic crossreactivity and physiologic function. The type II isoform encoded by this gene, is located in the mitochondria and expressed in extra-hepatic tissues, especially kidney. The physiologic role of this isoform is poorly understood; it is thought to play a role in nitric oxide and polyamine metabolism. Transcript variants of the type II gene resulting from the use of alternative polyadenylation sites have been described. [provided by RefSeq, Jul 2008]

GPHN (HGNC:15465): (gephyrin) This gene encodes a neuronal assembly protein that anchors inhibitory neurotransmitter receptors to the postsynaptic cytoskeleton via high affinity binding to a receptor subunit domain and tubulin dimers. In nonneuronal tissues, the encoded protein is also required for molybdenum cofactor biosynthesis. Mutations in this gene may be associated with the neurological condition hyperplexia and also lead to molybdenum cofactor deficiency. Numerous alternatively spliced transcript variants encoding different isoforms have been described; however, the full-length nature of all transcript variants is not currently known. [provided by RefSeq, Jul 2008]

GPHN Gene-Disease associations (from GenCC):

• sulfite oxidase deficiency due to molybdenum cofactor deficiency type C

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, ClinGen
• hereditary hyperekplexia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.22 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VTI1B	NM_006370.3	c.*681A>G		3_prime_UTR_variant	Exon 6 of 6	ENST00000554659.6	NP_006361.1
ARG2	NM_001172.4	c.860-11T>C		intron_variant	Intron 7 of 7	ENST00000261783.4	NP_001163.1
GPHN	XM_047430879.1	c.1313-84491T>C		intron_variant	Intron 14 of 14		XP_047286835.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VTI1B	ENST00000554659.6	c.*681A>G		3_prime_UTR_variant	Exon 6 of 6	1	NM_006370.3	ENSP00000450731.1
ARG2	ENST00000261783.4	c.860-11T>C		intron_variant	Intron 7 of 7	1	NM_001172.4	ENSP00000261783.3
ARG2	ENST00000557319.1	n.534-11T>C		intron_variant	Intron 3 of 3	2

Frequencies

GnomAD3 genomes AF: 0.0895 AC: 13620 AN: 152106 Hom.: 862 Cov.: 32

Gnomad AFR AF: 0.150

Gnomad AMI AF: 0.0779

Gnomad AMR AF: 0.145

Gnomad ASJ AF: 0.0369

Gnomad EAS AF: 0.230

Gnomad SAS AF: 0.0904

Gnomad FIN AF: 0.0247

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0429

Gnomad OTH AF: 0.0876

GnomAD2 exomes AF: 0.0917 AC: 22971 AN: 250396 AF XY: 0.0861

Gnomad AFR exome AF: 0.145

Gnomad AMR exome AF: 0.212

Gnomad ASJ exome AF: 0.0400

Gnomad EAS exome AF: 0.245

Gnomad FIN exome AF: 0.0247

Gnomad NFE exome AF: 0.0410

Gnomad OTH exome AF: 0.0702

GnomAD4 exome AF: 0.0574 AC: 83847 AN: 1460738 Hom.: 4226 Cov.: 31 AF XY: 0.0575 AC XY: 41763 AN XY: 726714

African (AFR) AF: 0.153 AC: 5127 AN: 33452

American (AMR) AF: 0.205 AC: 9154 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0417 AC: 1089 AN: 26126

East Asian (EAS) AF: 0.231 AC: 9152 AN: 39696

South Asian (SAS) AF: 0.0917 AC: 7908 AN: 86226

European-Finnish (FIN) AF: 0.0255 AC: 1364 AN: 53402

Middle Eastern (MID) AF: 0.0847 AC: 430 AN: 5074

European-Non Finnish (NFE) AF: 0.0408 AC: 45329 AN: 1111750

Other (OTH) AF: 0.0712 AC: 4294 AN: 60300

GnomAD4 genome AF: 0.0898 AC: 13673 AN: 152224 Hom.: 866 Cov.: 32 AF XY: 0.0904 AC XY: 6733 AN XY: 74446

African (AFR) AF: 0.150 AC: 6229 AN: 41528

American (AMR) AF: 0.145 AC: 2220 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0369 AC: 128 AN: 3470

East Asian (EAS) AF: 0.231 AC: 1192 AN: 5170

South Asian (SAS) AF: 0.0913 AC: 441 AN: 4828

European-Finnish (FIN) AF: 0.0247 AC: 262 AN: 10612

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.0429 AC: 2917 AN: 68022

Other (OTH) AF: 0.0890 AC: 188 AN: 2112

Alfa AF: 0.0649 Hom.: 107

Bravo AF: 0.105

Asia WGS AF: 0.166 AC: 576 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	15
DANN	Benign	0.75
PhyloP100		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000050
dbscSNV1_RF	Benign	0.020
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

Other links and lift over

dbSNP: rs10483802; hg19: chr14-68117421; COSMIC: COSV53619307; COSMIC: COSV53619307;