6-146434424-T-C

Position:

• chr6-146434424-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001278064.2(GRM1):​c.3213T>C​(p.Pro1071=) 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

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 789291.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-146434424-T-C is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRM1	NM_001278064.2	c.3213T>C	p.Pro1071=	synonymous_variant	8/8	ENST00000282753.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRM1	ENST00000282753.6	c.3213T>C	p.Pro1071=	synonymous_variant	8/8	1	NM_001278064.2	P1

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

GnomAD3 exomes AF: 0.00153 AC: 376 AN: 245168 Hom.: 0 AF XY: 0.00159 AC XY: 212 AN XY: 133690

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 SAS exome AF: 0.000196

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

Gnomad4 AFR exome AF: 0.000777

Gnomad4 AMR exome AF: 0.000783

Gnomad4 ASJ exome AF: 0.000613

Gnomad4 EAS exome AF: 0.000353

Gnomad4 SAS exome AF: 0.000243

Gnomad4 FIN exome AF: 0.00119

Gnomad4 NFE exome AF: 0.00244

Gnomad4 OTH exome AF: 0.00171

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

Gnomad4 AFR AF: 0.000939

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.000776

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00161

Gnomad4 NFE AF: 0.00352

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00177 Hom.: 1148

EpiCase AF: 0.00305

EpiControl AF: 0.00243

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 17, 2021	See Variant Classification Assertion Criteria. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	GRM1: BP4, BP7 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Feb 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.21
DANN	Benign	0.46

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

Publications

LitVar

Other links and lift over

dbSNP: rs1047006; hg19: chr6-146755560;