14-67656583-G-C

Variant names:

• chr14-67656583-G-C
• rs150325851
• NM_006370.3:c.373C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006370.3(VTI1B):​c.373C>G​(p.Leu125Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000159 in 1,447,428 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. 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. L125I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: VTI1B NM_006370.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.09
• Publications: 1 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]

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, ClinGen, Ambry Genetics
• hereditary hyperekplexia

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

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17163774).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VTI1B	NM_006370.3	MANE Select	c.373C>G	p.Leu125Val	missense	Exon 4 of 6	NP_006361.1	Q9UEU0-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VTI1B	ENST00000554659.6	TSL:1 MANE Select	c.373C>G	p.Leu125Val	missense	Exon 4 of 6	ENSP00000450731.1	Q9UEU0-1
	VTI1B	ENST00000216456.6	TSL:1	n.*400C>G		non_coding_transcript_exon	Exon 5 of 7	ENSP00000216456.6	J3KMW2
	VTI1B	ENST00000216456.6	TSL:1	n.*400C>G		3_prime_UTR	Exon 5 of 7	ENSP00000216456.6	J3KMW2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000415 AC: 1 AN: 240742 AF XY: 0.00000766

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000906

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000159 AC: 23 AN: 1447428 Hom.: 0 Cov.: 30 AF XY: 0.0000194 AC XY: 14 AN XY: 720152

African (AFR) AF: 0.00 AC: 0 AN: 32732

American (AMR) AF: 0.00 AC: 0 AN: 41236

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25384

East Asian (EAS) AF: 0.00 AC: 0 AN: 39538

South Asian (SAS) AF: 0.00 AC: 0 AN: 84450

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53124

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5686

European-Non Finnish (NFE) AF: 0.0000208 AC: 23 AN: 1105604

Other (OTH) AF: 0.00 AC: 0 AN: 59674

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.081	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.013
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		3.1
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.97	N
REVEL	Benign	0.083
Sift	Benign	0.12	T
Sift4G	Benign	0.25	T
Polyphen		0.051	B
Vest4		0.33
MutPred		0.53		Gain of catalytic residue at L125 (P = 0.0049)
MVP		0.048
MPC		0.34
ClinPred		0.25	T
GERP RS		5.6
Varity_R		0.055
gMVP		0.24
Mutation Taster		=76/24	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs150325851; hg19: chr14-68123300;