rs587780348

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS1

The NM_007327.4(GRIN1):c.1340C>A(p.Pro447His) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000366 in 1,612,232 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P447L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

GRIN1
NM_007327.4 missense, splice_region

Scores

Splicing: ADA: 0.002579

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 4.53

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 links:

LOC105376328 (HGNC:):

LOC105376328 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.21748239).

BP6

Variant 9-137161289-C-A is Benign according to our data. Variant chr9-137161289-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 403959.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1, Benign=1}.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000125 (19/152206) while in subpopulation AMR AF = 0.000981 (15/15286). AF 95% confidence interval is 0.000604. There are 0 homozygotes in GnomAd4. There are 11 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIN1	NM_007327.4 link	c.1340C>A	p.Pro447His	missense_variant, splice_region_variant	Exon 10 of 20	ENST00000371561.8	NP_015566.1	Q05586-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIN1	ENST00000371561.8 link	c.1340C>A	p.Pro447His	missense_variant, splice_region_variant	Exon 10 of 20	1	NM_007327.4	ENSP00000360616.3		Q05586-1

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000981

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000567

AC:

AN:

247074

AF XY:

0.0000446

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000261

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000454

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000274

AC:

AN:

1460026

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

726354

show subpopulations

Gnomad4 AFR exome

AF:

0.00

AC:

AN:

33452

Gnomad4 AMR exome

AF:

0.000224

AC:

AN:

44698

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

26100

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39674

Gnomad4 SAS exome

AF:

0.00

AC:

AN:

86250

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

52158

Gnomad4 NFE exome

AF:

0.0000261

AC:

AN:

1111592

Gnomad4 Remaining exome

AF:

0.0000166

AC:

AN:

60336

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome 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

GnomAD4 genome

AF:

0.000125

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.0000241

AC:

0.0000241231

AN:

0.0000241231

Gnomad4 AMR

AF:

0.000981

AC:

0.00098129

AN:

0.00098129

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.0000441

AC:

0.0000440904

AN:

0.0000440904

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.000189

ExAC

AF:

0.0000413

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 29, 2020

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Uncertain:1

Apr 26, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1340C>A (p.P447H) alteration is located in exon 10 (coding exon 10) of the GRIN1 gene. This alteration results from a C to A substitution at nucleotide position 1340, causing the proline (P) at amino acid position 447 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Benign:1

May 14, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Intellectual disability, autosomal dominant 8

Benign:1

Jan 11, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.48

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.47

T;.;.;T;.;.;.

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.14

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.83

T;T;T;T;T;T;T

M_CAP

Pathogenic

0.56

MetaRNN

Benign

0.22

T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.90

L;L;.;.;.;L;.

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-2.3

N;N;D;D;D;N;D

REVEL

Benign

0.081

Sift

Uncertain

0.029

D;D;T;D;D;D;T

Sift4G

Benign

0.12

T;T;T;T;T;T;T

Polyphen

0.38

B;P;.;.;.;P;.

Vest4

0.20

MutPred

0.45

Gain of catalytic residue at P447 (P = 0.0159);Gain of catalytic residue at P447 (P = 0.0159);.;.;.;Gain of catalytic residue at P447 (P = 0.0159);.;

MVP

0.36

MPC

1.5

ClinPred

0.25

GERP RS

1.9

Varity_R

0.24

gMVP

0.87

Mutation Taster

=43/57

disease causing

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0026

dbscSNV1_RF

Benign

0.096

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over