14-67648284-A-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006370.3(VTI1B):​c.*3101T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000825 in 1,212,272 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 8.2e-7 (0 hom.)
• Consequence: VTI1B NM_006370.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.33
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VTI1B	NM_006370.3	c.*3101T>A		3_prime_UTR_variant	Exon 6 of 6	ENST00000554659.6	NP_006361.1
ARG2	NM_001172.4	c.859+101A>T		intron_variant	Intron 7 of 7	ENST00000261783.4	NP_001163.1
GPHN	XM_047430879.1	c.1313-86911A>T		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.*3101T>A		3_prime_UTR_variant	Exon 6 of 6	1	NM_006370.3	ENSP00000450731.1
ARG2	ENST00000261783.4	c.859+101A>T		intron_variant	Intron 7 of 7	1	NM_001172.4	ENSP00000261783.3
ARG2	ENST00000557319.1	n.533+101A>T		intron_variant	Intron 3 of 3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.25e-7 AC: 1 AN: 1212272 Hom.: 0 Cov.: 16 AF XY: 0.00000167 AC XY: 1 AN XY: 598988

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 27126

American (AMR) AF: 0.00 AC: 0 AN: 25928

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19598

East Asian (EAS) AF: 0.00 AC: 0 AN: 36702

South Asian (SAS) AF: 0.00 AC: 0 AN: 61214

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40114

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4572

European-Non Finnish (NFE) AF: 0.00000106 AC: 1 AN: 946122

Other (OTH) AF: 0.00 AC: 0 AN: 50896

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	8.7
DANN	Benign	0.79
PhyloP100		2.3

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;