6-146434424-T-C

Variant names:

• chr6-146434424-T-C
• rs1047006
• NM_001278064.2:c.3213T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001278064.2(GRM1):​c.3213T>C​(p.Pro1071Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00206 in 1,613,228 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts 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. P1071P) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0021 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0021 (2 hom.)
• Consequence: GRM1 NM_001278064.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.40
• Publications: 13 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 6-146434424-T-C is Benign according to our data. Variant chr6-146434424-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 789291.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.4 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00209 (318/152152) while in subpopulation NFE AF = 0.00352 (239/67968). AF 95% confidence interval is 0.00315. There are 0 homozygotes in GnomAd4. There are 130 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR,AD gene

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.3213T>C	p.Pro1071Pro	synonymous	Exon 8 of 8	NP_001264993.1	Q13255-1
	GRM1	NM_001278067.1		c.*451T>C		3_prime_UTR	Exon 8 of 8	NP_001264996.1	Q59HC2
	GRM1	NM_001278065.2		c.*577T>C		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.3213T>C	p.Pro1071Pro	synonymous	Exon 8 of 8	ENSP00000282753.1	Q13255-1
	GRM1	ENST00000355289.8	TSL:1	c.*451T>C		3_prime_UTR	Exon 8 of 8	ENSP00000347437.4	Q13255-3
	GRM1	ENST00000492807.6	TSL:1	c.*577T>C		3_prime_UTR	Exon 10 of 10	ENSP00000424095.1	Q13255-2

Frequencies

GnomAD3 genomes AF: 0.00210 AC: 319 AN: 152036 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000774

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00161

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00352

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.00153 AC: 376 AN: 245168 AF XY: 0.00159

Gnomad AFR exome AF: 0.000787

Gnomad AMR exome AF: 0.000784

Gnomad ASJ exome AF: 0.000404

Gnomad EAS exome AF: 0.000666

Gnomad FIN exome AF: 0.00130

Gnomad NFE exome AF: 0.00252

Gnomad OTH exome AF: 0.00183

GnomAD4 exome AF: 0.00205 AC: 2999 AN: 1461076 Hom.: 2 Cov.: 54 AF XY: 0.00208 AC XY: 1510 AN XY: 726820

African (AFR) AF: 0.000777 AC: 26 AN: 33474

American (AMR) AF: 0.000783 AC: 35 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.000613 AC: 16 AN: 26104

East Asian (EAS) AF: 0.000353 AC: 14 AN: 39694

South Asian (SAS) AF: 0.000243 AC: 21 AN: 86246

European-Finnish (FIN) AF: 0.00119 AC: 63 AN: 53084

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.00244 AC: 2713 AN: 1111634

Other (OTH) AF: 0.00171 AC: 103 AN: 60364

GnomAD4 genome AF: 0.00209 AC: 318 AN: 152152 Hom.: 0 Cov.: 34 AF XY: 0.00175 AC XY: 130 AN XY: 74354

African (AFR) AF: 0.000939 AC: 39 AN: 41530

American (AMR) AF: 0.000719 AC: 11 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.000776 AC: 4 AN: 5154

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4824

European-Finnish (FIN) AF: 0.00161 AC: 17 AN: 10584

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

European-Non Finnish (NFE) AF: 0.00352 AC: 239 AN: 67968

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00177 Hom.: 1148

EpiCase AF: 0.00305

EpiControl AF: 0.00243

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.21
DANN	Benign	0.46
PhyloP100		-1.4
Mutation Taster		=100/0	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: rs1047006; hg19: chr6-146755560;