1-240870094-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001364886.1(RGS7):c.411G>C(p.Met137Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. M137L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RGS7 NM_001364886.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.79

Genes affected

RGS7 (HGNC:10003): (regulator of G protein signaling 7) Enables G-protein beta-subunit binding activity and GTPase activator activity. Involved in positive regulation of GTPase activity. Located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, RGS7
• BP4: Computational evidence support a benign effect (MetaRNN=0.41967767).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RGS7	NM_001364886.1	c.411G>C	p.Met137Ile	missense_variant	7/19	ENST00000440928.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RGS7	ENST00000440928.6	c.411G>C	p.Met137Ile	missense_variant	7/19	1	NM_001364886.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK:

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 22, 2021

The c.411G>C (p.M137I) alteration is located in exon 7 (coding exon 6) of the RGS7 gene. This alteration results from a G to C substitution at nucleotide position 411, causing the methionine (M) at amino acid position 137 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.14

D

BayesDel_noAF

Uncertain

-0.030

Cadd

Uncertain

26

Dann

Uncertain

0.99

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Pathogenic

0.99

D

LIST_S2

Uncertain

0.97

D;D;D;D

M_CAP

Benign

0.027

D

MetaRNN

Benign

0.42

T;T;T;T

MetaSVM

Benign

-1.1

T

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D

PrimateAI

Pathogenic

0.88

D

PROVEAN

Uncertain

-3.7

D;D;D;D

REVEL

Uncertain

0.31

Sift

Benign

0.16

T;T;T;T

Sift4G

Uncertain

0.026

D;T;T;T

Polyphen

0.99

D;B;B;P

Vest4

0.62

MVP

0.52

MPC

1.6

ClinPred

0.98

D

GERP RS

5.8

gMVP

0.71

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: chr1-241033394;