4-3316904-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_001394154.1(RGS12):c.734C>G(p.Ser245Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RGS12 NM_001394154.1 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.73

Genes affected

RGS12 (HGNC:9994): (regulator of G protein signaling 12) This gene encodes a member of the 'regulator of G protein signaling' (RGS) gene family. The encoded protein may function as a guanosine triphosphatase (GTPase)-activating protein as well as a transcriptional repressor. This protein may play a role in tumorigenesis. Multiple transcript variants encoding distinct isoforms have been identified for this gene. Other alternative splice variants have been described but their biological nature has not been determined. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.071269125).
• BP6: Variant 4-3316904-C-G is Benign according to our data. Variant chr4-3316904-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 3153822.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RGS12	NM_001394154.1	c.734C>G	p.Ser245Cys	missense_variant	2/18	ENST00000336727.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RGS12	ENST00000336727.8	c.734C>G	p.Ser245Cys	missense_variant	2/18	1	NM_001394154.1	P3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 47

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 27, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	17
Dann	Benign	0.92
DEOGEN2	Benign	0.051	T;.;T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.78	D
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.071	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N;N;N
MutationTaster	Benign	0.92	D;N;N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.2	N;N;N
REVEL	Benign	0.020
Sift	Benign	0.15	T;T;T
Sift4G	Benign	0.18	T;T;T
Polyphen		0.0050	B;B;B
Vest4		0.097
MutPred		0.28		Loss of disorder (P = 0.0139);Loss of disorder (P = 0.0139);Loss of disorder (P = 0.0139);
MVP		0.39
MPC		0.18
ClinPred		0.12	T
GERP RS		2.8
Varity_R		0.049
gMVP		0.55

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-3318631;