6-146352506-T-C

Variant names:

• chr6-146352506-T-C
• rs373538200
• NM_001278064.2:c.1433+10T>C

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.1433+10T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00144 in 1,613,110 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00097 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (1 hom.)
• Consequence: GRM1 NM_001278064.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.438
• 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: Labcorp Genetics (formerly Invitae), Orphanet, G2P

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 6-146352506-T-C is Benign according to our data. Variant chr6-146352506-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 447457.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000966 (147/152180) while in subpopulation NFE AF = 0.00173 (118/68034). AF 95% confidence interval is 0.00148. There are 0 homozygotes in GnomAd4. There are 69 alleles in the male GnomAd4 subpopulation. Median coverage is 32. 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.1433+10T>C		intron	N/A	NP_001264993.1
	GRM1	NM_001278067.1		c.1433+10T>C		intron	N/A	NP_001264996.1
	GRM1	NM_001278065.2		c.1433+10T>C		intron	N/A	NP_001264994.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRM1	ENST00000282753.6	TSL:1 MANE Select	c.1433+10T>C		intron	N/A	ENSP00000282753.1
	GRM1	ENST00000355289.8	TSL:1	c.1433+10T>C		intron	N/A	ENSP00000347437.4
	GRM1	ENST00000492807.6	TSL:1	c.1433+10T>C		intron	N/A	ENSP00000424095.1

Frequencies

GnomAD3 genomes AF: 0.000966 AC: 147 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00173

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00108 AC: 270 AN: 248872 AF XY: 0.00111

Gnomad AFR exome AF: 0.000558

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000694

Gnomad NFE exome AF: 0.00209

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.00149 AC: 2172 AN: 1460930 Hom.: 1 Cov.: 31 AF XY: 0.00145 AC XY: 1056 AN XY: 726796

African (AFR) AF: 0.000149 AC: 5 AN: 33472

American (AMR) AF: 0.000134 AC: 6 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85928

European-Finnish (FIN) AF: 0.00144 AC: 77 AN: 53298

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5748

European-Non Finnish (NFE) AF: 0.00180 AC: 2004 AN: 1111568

Other (OTH) AF: 0.00128 AC: 77 AN: 60372

GnomAD4 genome AF: 0.000966 AC: 147 AN: 152180 Hom.: 0 Cov.: 32 AF XY: 0.000928 AC XY: 69 AN XY: 74340

African (AFR) AF: 0.000386 AC: 16 AN: 41442

American (AMR) AF: 0.000131 AC: 2 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

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

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00173 AC: 118 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00115 Hom.: 0

Bravo AF: 0.000907

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	6.1
DANN	Benign	0.62
PhyloP100		0.44
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: rs373538200; hg19: chr6-146673642;