6-146434417-C-T

Position:

chr6-146434417-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_001278064.2(GRM1):c.3206C>T(p.Pro1069Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00127 in 1,613,554 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0032 ( 1 hom., cov: 34)

Exomes 𝑓: 0.0011 ( 5 hom. )

Consequence

GRM1
NM_001278064.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 2.28

Variant links:

Genes affected

GRM1 (HGNC:4593): (glutamate metabotropic receptor 1) This gene encodes a metabotropic glutamate receptor that functions by activating phospholipase C. L-glutamate is the major excitatory neurotransmitter in the central nervous system and activates both ionotropic and metabotropic glutamate receptors. Glutamatergic neurotransmission is involved in most aspects of normal brain function and can be perturbed in many neuropathologic conditions. The canonical alpha isoform of the encoded protein is a disulfide-linked homodimer whose activity is mediated by a G-protein-coupled phosphatidylinositol-calcium second messenger system. This gene may be associated with many disease states, including schizophrenia, bipolar disorder, depression, and breast cancer. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, May 2013]

GRM1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), GRM1. . Gene score misZ 2.5817 (greater than the threshold 3.09). Trascript score misZ 3.6372 (greater than threshold 3.09). GenCC has associacion of gene with spinocerebellar ataxia 44, autosomal recessive spinocerebellar ataxia 13.

BP4

Computational evidence support a benign effect (MetaRNN=0.00431031).

BP6

Variant 6-146434417-C-T is Benign according to our data. Variant chr6-146434417-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 447464.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-146434417-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00322 (491/152342) while in subpopulation AFR AF= 0.00741 (308/41584). AF 95% confidence interval is 0.00673. There are 1 homozygotes in gnomad4. There are 245 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRM1	NM_001278064.2 linkuse as main transcript	c.3206C>T	p.Pro1069Leu	missense_variant	8/8	ENST00000282753.6	NP_001264993.1	Q13255-1Q59HC2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRM1	ENST00000282753.6 linkuse as main transcript	c.3206C>T	p.Pro1069Leu	missense_variant	8/8	1	NM_001278064.2	ENSP00000282753.1		Q13255-1

Frequencies

GnomAD3 genomes

AF:

0.00323

AC:

491

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00743

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00550

Gnomad ASJ

AF:

0.00778

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000941

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00171

AC:

418

AN:

244354

Hom.:

AF XY:

0.00169

AC XY:

226

AN XY:

133408

show subpopulations

Gnomad AFR exome

AF:

0.00850

Gnomad AMR exome

AF:

0.00296

Gnomad ASJ exome

AF:

0.00720

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000983

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000964

Gnomad OTH exome

AF:

0.00150

GnomAD4 exome

AF:

0.00107

AC:

1565

AN:

1461212

Hom.:

Cov.:

AF XY:

0.00105

AC XY:

760

AN XY:

726904

show subpopulations

Gnomad4 AFR exome

AF:

0.00807

Gnomad4 AMR exome

AF:

0.00300

Gnomad4 ASJ exome

AF:

0.00667

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000733

Gnomad4 OTH exome

AF:

0.00235

GnomAD4 genome

AF:

0.00322

AC:

491

AN:

152342

Hom.:

Cov.:

AF XY:

0.00329

AC XY:

245

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.00741

Gnomad4 AMR

AF:

0.00549

Gnomad4 ASJ

AF:

0.00778

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000941

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00132

Hom.:

Bravo

AF:

0.00377

ExAC

AF:

0.00173

AC:

210

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00104

EpiControl

AF:

0.000948

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 12, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 05, 2019	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.13

T;T

Eigen

Benign

-0.11

Eigen_PC

Benign

0.070

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.64

T;.

MetaRNN

Benign

0.0043

T;T

MetaSVM

Benign

-0.57

MutationAssessor

Benign

0.55

N;N

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.24

N;N

REVEL

Uncertain

0.29

Sift

Benign

0.63

T;T

Sift4G

Benign

0.55

T;T

Polyphen

0.0

B;B

Vest4

0.34

MVP

0.30

MPC

0.71

ClinPred

0.012

GERP RS

4.8

Varity_R

0.097

gMVP

0.51

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over