rs747916965

Variant names:

• chr1-235552189-G-A
• rs747916965
• NM_001098722.2:c.148C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-235552189-G-A
• chr1-235552189-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001098722.2(GNG4):​c.148C>T​(p.Arg50Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,461,316 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R50Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: GNG4 NM_001098722.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.73
• Publications: 5 publications found

Genes affected

GNG4 (HGNC:4407): (G protein subunit gamma 4) Predicted to enable G-protein beta-subunit binding activity. Involved in negative regulation of cell growth. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3802907).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001098722.2. 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
	GNG4	NM_001098722.2	MANE Select	c.148C>T	p.Arg50Trp	missense	Exon 4 of 4	NP_001092192.1	P50150
	GNG4	NM_001098721.2		c.148C>T	p.Arg50Trp	missense	Exon 4 of 4	NP_001092191.1	B1APZ0
	GNG4	NM_004485.4		c.148C>T	p.Arg50Trp	missense	Exon 3 of 3	NP_004476.1	P50150

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNG4	ENST00000391854.7	TSL:1 MANE Select	c.148C>T	p.Arg50Trp	missense	Exon 4 of 4	ENSP00000375727.2	P50150
	GNG4	ENST00000366597.5	TSL:1	c.148C>T	p.Arg50Trp	missense	Exon 3 of 3	ENSP00000355556.1	P50150
	GNG4	ENST00000366598.8	TSL:1	c.148C>T	p.Arg50Trp	missense	Exon 3 of 3	ENSP00000355557.4	P50150

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251120 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000109 AC: 16 AN: 1461316 Hom.: 0 Cov.: 29 AF XY: 0.00000963 AC XY: 7 AN XY: 727006

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

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

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

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

European-Non Finnish (NFE) AF: 0.00000900 AC: 10 AN: 1111528

Other (OTH) AF: 0.0000497 AC: 3 AN: 60370

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Benign	0.68	D
M_CAP	Benign	0.076	D
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-1.0	T
PhyloP100		1.7
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Benign	0.11
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.012	D
Polyphen		1.0	D
Vest4		0.15
MutPred		0.38		Gain of catalytic residue at P53 (P = 0.0319)
MVP		0.85
MPC		0.68
ClinPred		0.97	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.19
gMVP		0.73
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs747916965; hg19: chr1-235715489; COSMIC: COSV63998919;