chr6-146434372-G-A

Variant names:

• chr6-146434372-G-A
• rs145764886
• NM_001278064.2:c.3161G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_001278064.2(GRM1):​c.3161G>A​(p.Gly1054Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000314 in 1,613,290 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G1054G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: GRM1 NM_001278064.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.331
• 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: G2P, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0032530427).
• BP6: Variant 6-146434372-G-A is Benign according to our data. Variant chr6-146434372-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 447463.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00175 (267/152336) while in subpopulation AFR AF = 0.00628 (261/41580). AF 95% confidence interval is 0.00565. There are 1 homozygotes in GnomAd4. There are 114 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.3161G>A	p.Gly1054Asp	missense	Exon 8 of 8	NP_001264993.1	Q13255-1
	GRM1	NM_001278067.1		c.*399G>A		3_prime_UTR	Exon 8 of 8	NP_001264996.1	Q59HC2
	GRM1	NM_001278065.2		c.*525G>A		3_prime_UTR	Exon 10 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.3161G>A	p.Gly1054Asp	missense	Exon 8 of 8	ENSP00000282753.1	Q13255-1
	GRM1	ENST00000355289.8	TSL:1	c.*399G>A		3_prime_UTR	Exon 8 of 8	ENSP00000347437.4	Q13255-3
	GRM1	ENST00000492807.6	TSL:1	c.*525G>A		3_prime_UTR	Exon 10 of 10	ENSP00000424095.1	Q13255-2

Frequencies

GnomAD3 genomes AF: 0.00175 AC: 266 AN: 152218 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00627

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.00

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000442 AC: 108 AN: 244218 AF XY: 0.000300

Gnomad AFR exome AF: 0.00658

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000919

Gnomad OTH exome AF: 0.000503

GnomAD4 exome AF: 0.000164 AC: 240 AN: 1460954 Hom.: 0 Cov.: 37 AF XY: 0.000143 AC XY: 104 AN XY: 726704

African (AFR) AF: 0.00645 AC: 216 AN: 33472

American (AMR) AF: 0.000157 AC: 7 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26084

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86192

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53126

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111568

Other (OTH) AF: 0.000249 AC: 15 AN: 60360

GnomAD4 genome AF: 0.00175 AC: 267 AN: 152336 Hom.: 1 Cov.: 33 AF XY: 0.00153 AC XY: 114 AN XY: 74482

African (AFR) AF: 0.00628 AC: 261 AN: 41580

American (AMR) AF: 0.000261 AC: 4 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000448 Hom.: 0

Bravo AF: 0.00204

ESP6500AA AF: 0.00455 AC: 20

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000528 AC: 64

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Autosomal recessive spinocerebellar ataxia 13;C4521563:Spinocerebellar ataxia 44 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	12
DANN	Benign	0.91
DEOGEN2	Benign	0.097	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.0033	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.33
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.67	N
REVEL	Benign	0.14
Sift	Benign	0.63	T
Sift4G	Benign	0.63	T
Polyphen		0.0030	B
Vest4		0.10
MVP		0.30
MPC		0.92
ClinPred		0.0014	T
GERP RS		-1.3
Varity_R		0.061
gMVP		0.49
Mutation Taster		=98/2	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: rs145764886; hg19: chr6-146755508;