NM_001172.4:c.1052G>T

Variant names:

• chr14-67650907-G-T
• rs762859411
• NM_001172.4:c.1052G>T

Variant summary

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

The NM_001172.4(ARG2):​c.1052G>T​(p.Arg351Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,714 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. R351H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ARG2 NM_001172.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.58
• Publications: 0 publications found

Genes affected

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]

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: G2P, ClinGen, Labcorp Genetics (formerly Invitae), 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=0.13140306).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001172.4. 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
	ARG2	NM_001172.4	MANE Select	c.1052G>T	p.Arg351Leu	missense	Exon 8 of 8	NP_001163.1	P78540
	VTI1B	NM_006370.3	MANE Select	c.*478C>A		3_prime_UTR	Exon 6 of 6	NP_006361.1	Q9UEU0-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARG2	ENST00000261783.4	TSL:1 MANE Select	c.1052G>T	p.Arg351Leu	missense	Exon 8 of 8	ENSP00000261783.3	P78540
	VTI1B	ENST00000554659.6	TSL:1 MANE Select	c.*478C>A		3_prime_UTR	Exon 6 of 6	ENSP00000450731.1	Q9UEU0-1
	ARG2	ENST00000927904.1		c.947G>T	p.Arg316Leu	missense	Exon 7 of 7	ENSP00000597963.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461714 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727160

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53330

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111950

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.051	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	1.6	L
PhyloP100		1.6
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.88	N
REVEL	Benign	0.13
Sift	Benign	0.093	T
Sift4G	Benign	0.19	T
Polyphen		0.0	B
Vest4		0.13
MutPred		0.33		Loss of sheet (P = 0.1158)
MVP		0.40
MPC		0.22
ClinPred		0.44	T
GERP RS		3.5
Varity_R		0.048
gMVP		0.50
Mutation Taster		=95/5	polymorphism

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: rs762859411; hg19: chr14-68117624;