chr9-137139197-AGCC-A

Variant names:

• chr9-137139197-AGCC-A
• rs763024426
• ENST00000350902.9:n.-273_-271delCCG

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The ENST00000350902.9(GRIN1):​n.-273_-271delCCG variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00293 in 157,670 control chromosomes in the GnomAD database, including 3 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0026 (3 hom., cov: 32)
  • Exomes 𝑓: 0.010 (0 hom.)
• Consequence: GRIN1 ENST00000350902.9 non_coding_transcript_exon
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.299
• Publications: 0 publications found

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

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00264 (401/151664) while in subpopulation EAS AF = 0.00816 (42/5148). AF 95% confidence interval is 0.0062. There are 3 homozygotes in GnomAd4. There are 247 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIN1	NM_007327.4	c.-273_-271delCCG		5_prime_UTR_variant	Exon 1 of 20	ENST00000371561.8	NP_015566.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIN1	ENST00000371561.8	c.-273_-271delCCG		5_prime_UTR_variant	Exon 1 of 20	1	NM_007327.4	ENSP00000360616.3

Frequencies

GnomAD3 genomes AF: 0.00265 AC: 401 AN: 151558 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00114

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00813

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.0235

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000752

Gnomad OTH AF: 0.000479

GnomAD4 exome AF: 0.0102 AC: 61 AN: 6006 Hom.: 0 AF XY: 0.0105 AC XY: 37 AN XY: 3518

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 102

American (AMR) AF: 0.0102 AC: 2 AN: 196

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 90

East Asian (EAS) AF: 0.0278 AC: 5 AN: 180

South Asian (SAS) AF: 0.00346 AC: 3 AN: 868

European-Finnish (FIN) AF: 0.0360 AC: 24 AN: 666

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 26

European-Non Finnish (NFE) AF: 0.00753 AC: 27 AN: 3588

Other (OTH) AF: 0.00 AC: 0 AN: 290

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000001), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00264 AC: 401 AN: 151664 Hom.: 3 Cov.: 32 AF XY: 0.00333 AC XY: 247 AN XY: 74122

African (AFR) AF: 0.00113 AC: 47 AN: 41434

American (AMR) AF: 0.000262 AC: 4 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00816 AC: 42 AN: 5148

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4830

European-Finnish (FIN) AF: 0.0235 AC: 245 AN: 10426

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000752 AC: 51 AN: 67792

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.00162 Hom.: 0

Bravo AF: 0.00103

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 28, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.30
Mutation Taster		=296/4	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs763024426; hg19: chr9-140033649;