rs199777173

Variant names:

• chr6-146434255-C-A
• rs199777173
• NM_001278064.2:c.3044C>A

Your query was ambiguous. Multiple possible variants found:

• chr6-146434255-C-A
• chr6-146434255-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001278064.2(GRM1):​c.3044C>A​(p.Pro1015His) 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. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1015R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GRM1 NM_001278064.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.70
• Publications: 1 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: Labcorp Genetics (formerly Invitae), Orphanet, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18152538).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRM1	NM_001278064.2	MANE Select	c.3044C>A	p.Pro1015His	missense	Exon 8 of 8	NP_001264993.1
	GRM1	NM_001278067.1		c.*282C>A		3_prime_UTR	Exon 8 of 8	NP_001264996.1
	GRM1	NM_001278065.2		c.*408C>A		3_prime_UTR	Exon 10 of 10	NP_001264994.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRM1	ENST00000282753.6	TSL:1 MANE Select	c.3044C>A	p.Pro1015His	missense	Exon 8 of 8	ENSP00000282753.1
	GRM1	ENST00000355289.8	TSL:1	c.*282C>A		3_prime_UTR	Exon 8 of 8	ENSP00000347437.4
	GRM1	ENST00000492807.6	TSL:1	c.*408C>A		3_prime_UTR	Exon 10 of 10	ENSP00000424095.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.041	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.29	T
M_CAP	Pathogenic	0.31	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	0.34	N
PhyloP100		1.7
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.76	N
REVEL	Benign	0.27
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.66	P
Vest4		0.32
MutPred		0.21		Loss of glycosylation at P1015 (P = 0.0048)
MVP		0.36
MPC		0.85
ClinPred		0.38	T
GERP RS		4.1
Varity_R		0.10
gMVP		0.39
Mutation Taster		=79/21	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: rs199777173; hg19: chr6-146755391;