chr14-67648284-A-G

Variant names:

• chr14-67648284-A-G
• rs3742879
• NM_006370.3:c.*3101T>C

Variant summary

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

The NM_006370.3(VTI1B):​c.*3101T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.268 in 1,362,416 control chromosomes in the GnomAD database, including 55,030 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 0.21 (4278 hom., cov: 32)
  • Exomes 𝑓: 0.28 (50752 hom.)
• Consequence: VTI1B NM_006370.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.33
• Publications: 22 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=-0.83).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.309 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006370.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VTI1B	NM_006370.3	MANE Select	c.*3101T>C		3_prime_UTR	Exon 6 of 6	NP_006361.1
	ARG2	NM_001172.4	MANE Select	c.859+101A>G		intron	N/A	NP_001163.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VTI1B	ENST00000554659.6	TSL:1 MANE Select	c.*3101T>C		3_prime_UTR	Exon 6 of 6	ENSP00000450731.1
	ARG2	ENST00000261783.4	TSL:1 MANE Select	c.859+101A>G		intron	N/A	ENSP00000261783.3
	ARG2	ENST00000557319.1	TSL:2	n.533+101A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.209 AC: 31728 AN: 152038 Hom.: 4280 Cov.: 32

Gnomad AFR AF: 0.0602

Gnomad AMI AF: 0.232

Gnomad AMR AF: 0.214

Gnomad ASJ AF: 0.220

Gnomad EAS AF: 0.0150

Gnomad SAS AF: 0.0951

Gnomad FIN AF: 0.260

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.312

Gnomad OTH AF: 0.202

GnomAD4 exome AF: 0.276 AC: 333927 AN: 1210260 Hom.: 50752 Cov.: 16 AF XY: 0.272 AC XY: 162923 AN XY: 598060

African (AFR) AF: 0.0446 AC: 1209 AN: 27114

American (AMR) AF: 0.234 AC: 6053 AN: 25896

Ashkenazi Jewish (ASJ) AF: 0.206 AC: 4025 AN: 19570

East Asian (EAS) AF: 0.0226 AC: 829 AN: 36698

South Asian (SAS) AF: 0.100 AC: 6141 AN: 61160

European-Finnish (FIN) AF: 0.265 AC: 10612 AN: 40058

Middle Eastern (MID) AF: 0.145 AC: 663 AN: 4568

European-Non Finnish (NFE) AF: 0.309 AC: 291897 AN: 944362

Other (OTH) AF: 0.246 AC: 12498 AN: 50834

GnomAD4 genome AF: 0.209 AC: 31725 AN: 152156 Hom.: 4278 Cov.: 32 AF XY: 0.203 AC XY: 15111 AN XY: 74370

African (AFR) AF: 0.0601 AC: 2496 AN: 41532

American (AMR) AF: 0.214 AC: 3266 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.220 AC: 763 AN: 3472

East Asian (EAS) AF: 0.0152 AC: 79 AN: 5194

South Asian (SAS) AF: 0.0954 AC: 461 AN: 4832

European-Finnish (FIN) AF: 0.260 AC: 2746 AN: 10568

Middle Eastern (MID) AF: 0.197 AC: 58 AN: 294

European-Non Finnish (NFE) AF: 0.312 AC: 21224 AN: 67960

Other (OTH) AF: 0.199 AC: 421 AN: 2112

Alfa AF: 0.271 Hom.: 16723

Bravo AF: 0.196

Asia WGS AF: 0.0620 AC: 218 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	8.7
DANN	Benign	0.81
PhyloP100		2.3
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: rs3742879; hg19: chr14-68115001;