Genetic Variant GRIN1:c.570+10G>A (chr9-137145912-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001437330.1(GRIN1):c.570+10G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000743 in 1,586,810 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00083 ( 1 hom., cov: 34)

Exomes 𝑓: 0.00073 ( 9 hom. )

Consequence

GRIN1
NM_001437330.1 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.414

Publications

0 publications found

Variant links:

Genes affected

GRIN1 (HGNC:4584): (glutamate ionotropic receptor NMDA type subunit 1) The protein encoded by this gene is a critical subunit of N-methyl-D-aspartate receptors, members of the glutamate receptor channel superfamily which are heteromeric protein complexes with multiple subunits arranged to form a ligand-gated ion channel. These subunits play a key role in the plasticity of synapses, which is believed to underlie memory and learning. Cell-specific factors are thought to control expression of different isoforms, possibly contributing to the functional diversity of the subunits. Alternatively spliced transcript variants have been described. [provided by RefSeq, Jul 2008]

GRIN1 Gene-Disease associations (from GenCC):

neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
complex neurodevelopmental disorder
Inheritance: AR, AD Classification: DEFINITIVE Submitted by: ClinGen
neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive
Inheritance: AR Classification: DEFINITIVE, MODERATE Submitted by: G2P, Ambry Genetics
developmental and epileptic encephalopathy 101
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
autosomal dominant non-syndromic intellectual disability
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

GRIN1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 9-137145912-G-A is Benign according to our data. Variant chr9-137145912-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 388019.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000828 (126/152214) while in subpopulation SAS AF = 0.00207 (10/4828). AF 95% confidence interval is 0.00112. There are 1 homozygotes in GnomAd4. There are 57 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 9 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001437330.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
GRIN1	NM_007327.4	MANE Select	c.570+10G>A	intron	N/A	NP_015566.1
GRIN1	NM_001437330.1		c.570+10G>A	intron	N/A	NP_001424259.1
GRIN1	NM_001185090.2		c.570+10G>A	intron	N/A	NP_001172019.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
GRIN1	ENST00000371561.8	TSL:1 MANE Select	c.570+10G>A	intron	N/A	ENSP00000360616.3
GRIN1	ENST00000371553.8	TSL:1	c.570+10G>A	intron	N/A	ENSP00000360608.3
GRIN1	ENST00000371560.5	TSL:1	c.570+10G>A	intron	N/A	ENSP00000360615.3

Frequencies

GnomAD3 genomes

AF:

0.000828

AC:

126

AN:

152096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.0242

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000294

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00166

AC:

330

AN:

199148

AF XY:

0.00182

show subpopulations

Gnomad AFR exome

AF:

0.0000854

Gnomad AMR exome

AF:

0.0000340

Gnomad ASJ exome

AF:

0.0222

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000594

Gnomad NFE exome

AF:

0.000570

Gnomad OTH exome

AF:

0.00332

GnomAD4 exome

AF:

0.000734

AC:

1053

AN:

1434596

Hom.:

Cov.:

AF XY:

0.000845

AC XY:

601

AN XY:

711560

show subpopulations

African (AFR)

AF:

0.0000303

AC:

AN:

32952

American (AMR)

AF:

0.0000978

AC:

AN:

40920

Ashkenazi Jewish (ASJ)

AF:

0.0194

AC:

497

AN:

25604

East Asian (EAS)

AF:

0.00

AC:

AN:

38370

South Asian (SAS)

AF:

0.00218

AC:

181

AN:

82910

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50438

Middle Eastern (MID)

AF:

0.00526

AC:

AN:

5708

European-Non Finnish (NFE)

AF:

0.000201

AC:

221

AN:

1098358

Other (OTH)

AF:

0.00201

AC:

119

AN:

59336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

124

186

248

310

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000828

AC:

126

AN:

152214

Hom.:

Cov.:

AF XY:

0.000766

AC XY:

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41514

American (AMR)

AF:

0.000131

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0242

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000294

AC:

AN:

67980

Other (OTH)

AF:

0.00189

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00384

Hom.:

Bravo

AF:

0.000835

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

7.8

(source)

DANN

Benign

0.96

PhyloP100

-0.41

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over