rs10483801

Variant names:

• chr14-67650289-C-A
• rs10483801
• NM_006370.3:c.*1096G>T

Variant summary

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

The NM_006370.3(VTI1B):​c.*1096G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.238 in 223,168 control chromosomes in the GnomAD database, including 7,355 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 0.26 (5645 hom., cov: 32)
  • Exomes 𝑓: 0.20 (1710 hom.)
• Consequence: VTI1B NM_006370.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.107
• Publications: 28 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=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.433 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VTI1B	NM_006370.3	c.*1096G>T		3_prime_UTR_variant	Exon 6 of 6	ENST00000554659.6	NP_006361.1
ARG2	NM_001172.4	c.860-426C>A		intron_variant	Intron 7 of 7	ENST00000261783.4	NP_001163.1
GPHN	XM_047430879.1	c.1313-84906C>A		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.*1096G>T		3_prime_UTR_variant	Exon 6 of 6	1	NM_006370.3	ENSP00000450731.1
ARG2	ENST00000261783.4	c.860-426C>A		intron_variant	Intron 7 of 7	1	NM_001172.4	ENSP00000261783.3
ARG2	ENST00000557319.1	n.534-426C>A		intron_variant	Intron 3 of 3	2

Frequencies

GnomAD3 genomes AF: 0.256 AC: 38901 AN: 151872 Hom.: 5623 Cov.: 32

Gnomad AFR AF: 0.372

Gnomad AMI AF: 0.146

Gnomad AMR AF: 0.312

Gnomad ASJ AF: 0.205

Gnomad EAS AF: 0.449

Gnomad SAS AF: 0.198

Gnomad FIN AF: 0.183

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.179

Gnomad OTH AF: 0.251

GnomAD4 exome AF: 0.199 AC: 14193 AN: 71178 Hom.: 1710 Cov.: 0 AF XY: 0.195 AC XY: 7125 AN XY: 36498

African (AFR) AF: 0.353 AC: 628 AN: 1778

American (AMR) AF: 0.346 AC: 1344 AN: 3888

Ashkenazi Jewish (ASJ) AF: 0.187 AC: 314 AN: 1676

East Asian (EAS) AF: 0.440 AC: 1617 AN: 3674

South Asian (SAS) AF: 0.182 AC: 1601 AN: 8796

European-Finnish (FIN) AF: 0.170 AC: 531 AN: 3122

Middle Eastern (MID) AF: 0.215 AC: 62 AN: 288

European-Non Finnish (NFE) AF: 0.167 AC: 7352 AN: 44148

Other (OTH) AF: 0.195 AC: 744 AN: 3808

GnomAD4 genome AF: 0.257 AC: 38987 AN: 151990 Hom.: 5645 Cov.: 32 AF XY: 0.256 AC XY: 18981 AN XY: 74266

African (AFR) AF: 0.373 AC: 15428 AN: 41414

American (AMR) AF: 0.313 AC: 4774 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.205 AC: 712 AN: 3468

East Asian (EAS) AF: 0.449 AC: 2310 AN: 5150

South Asian (SAS) AF: 0.199 AC: 958 AN: 4812

European-Finnish (FIN) AF: 0.183 AC: 1934 AN: 10584

Middle Eastern (MID) AF: 0.207 AC: 61 AN: 294

European-Non Finnish (NFE) AF: 0.178 AC: 12133 AN: 67972

Other (OTH) AF: 0.258 AC: 544 AN: 2112

Alfa AF: 0.186 Hom.: 1806

Bravo AF: 0.278

Asia WGS AF: 0.347 AC: 1204 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.0
DANN	Benign	0.38
PhyloP100		-0.11
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10483801; hg19: chr14-68117006;