9-137139508-A-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 BP4 BP6_Very_Strong

The NM_007327.4(GRIN1):c.22A>C(p.Thr8Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000152 in 1,447,152 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T8M) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: GRIN1 NM_007327.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.35

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• PP2: Missense variant where missense usually causes diseases, GRIN1
• BP4: Computational evidence support a benign effect (MetaRNN=0.2738123).
• BP6: Variant 9-137139508-A-C is Benign according to our data. Variant chr9-137139508-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 562038.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIN1	NM_007327.4	c.22A>C	p.Thr8Pro	missense_variant	1/20	ENST00000371561.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIN1	ENST00000371561.8	c.22A>C	p.Thr8Pro	missense_variant	1/20	1	NM_007327.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000847 AC: 2 AN: 236044 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 129674

Gnomad AFR exome AF: 0.0000672

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000942

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000152 AC: 22 AN: 1447152 Hom.: 0 Cov.: 32 AF XY: 0.0000153 AC XY: 11 AN XY: 718196

Gnomad4 AFR exome AF: 0.0000601

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000314 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000826 AC: 1

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2017

- -

Intellectual disability, autosomal dominant 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 04, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	20
Dann	Uncertain	0.98
DEOGEN2	Benign	0.37	T;.;.;T;.;.;.
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.77	T;T;T;T;T;T;T
M_CAP	Pathogenic	0.62	D
MetaRNN	Benign	0.27	T;T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.0	N;N;N;.;N;N;N
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-2.1	N;N;N;N;N;N;N
REVEL	Benign	0.067
Sift	Benign	0.12	T;T;T;T;T;T;T
Sift4G	Benign	0.10	T;T;T;T;T;T;T
Polyphen		0.20	B;P;.;.;.;B;.
Vest4		0.21
MutPred		0.48		Gain of helix (P = 0.027);Gain of helix (P = 0.027);Gain of helix (P = 0.027);Gain of helix (P = 0.027);Gain of helix (P = 0.027);Gain of helix (P = 0.027);Gain of helix (P = 0.027);
MVP		0.58
MPC		1.6
ClinPred		0.077	T
GERP RS		-0.24
Varity_R		0.38
gMVP		0.64

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: rs768572879; hg19: chr9-140033960;