6-146029558-T-G

Variant names:

• chr6-146029558-T-G
• rs774851565
• NM_001278064.2:c.41T>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_001278064.2(GRM1):​c.41T>G​(p.Leu14Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000204 in 1,613,962 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: GRM1 NM_001278064.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.76
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• spinocerebellar ataxia 44

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• autosomal recessive spinocerebellar ataxia 13

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.30720317).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001278064.2. 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
	GRM1	NM_001278064.2	MANE Select	c.41T>G	p.Leu14Trp	missense	Exon 1 of 8	NP_001264993.1	Q13255-1
	GRM1	NM_001278067.1		c.41T>G	p.Leu14Trp	missense	Exon 1 of 8	NP_001264996.1	Q59HC2
	GRM1	NM_001278065.2		c.41T>G	p.Leu14Trp	missense	Exon 2 of 10	NP_001264994.1	Q13255-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRM1	ENST00000282753.6	TSL:1 MANE Select	c.41T>G	p.Leu14Trp	missense	Exon 1 of 8	ENSP00000282753.1	Q13255-1
	GRM1	ENST00000355289.8	TSL:1	c.41T>G	p.Leu14Trp	missense	Exon 1 of 8	ENSP00000347437.4	Q13255-3
	GRM1	ENST00000492807.6	TSL:1	c.41T>G	p.Leu14Trp	missense	Exon 2 of 10	ENSP00000424095.1	Q13255-2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152094 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251032 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000212 AC: 31 AN: 1461868 Hom.: 0 Cov.: 32 AF XY: 0.0000248 AC XY: 18 AN XY: 727236

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

American (AMR) AF: 0.00 AC: 0 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

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

European-Non Finnish (NFE) AF: 0.0000279 AC: 31 AN: 1111988

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152094 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74298

African (AFR) AF: 0.00 AC: 0 AN: 41404

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2080

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Uncertain	0.077	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	20
DANN	Benign	0.88
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.082
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.078	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	1.6	L
PhyloP100		3.8
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.88	N
REVEL	Uncertain	0.47
Sift	Benign	0.037	D
Sift4G	Uncertain	0.013	D
Polyphen		0.82	P
Vest4		0.27
MutPred		0.59		Gain of catalytic residue at L14 (P = 0.0082)
MVP		0.55
MPC		1.9
ClinPred		0.41	T
GERP RS		3.0
PromoterAI		0.026	Neutral
Varity_R		0.046
gMVP		0.46
Mutation Taster		=84/16	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: rs774851565; hg19: chr6-146350694;