19-38537958-A-T

Variant names:

• chr19-38537958-A-T
• rs1555793251
• NM_000540.3:c.11687A>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM1

The ENST00000359596.8(RYR1):​c.11687A>T​(p.Asn3896Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N3896S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000014 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00043 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RYR1 ENST00000359596.8 missense
• Scores: Splicing: ADA: 0.1238
• Clinical Significance: Uncertain significance criteria provided, single submitter U:4
• Conservation: PhyloP100: 2.16
• Publications: 0 publications found

Genes affected

RYR1 (HGNC:10483): (ryanodine receptor 1) This gene encodes a ryanodine receptor found in skeletal muscle. The encoded protein functions as a calcium release channel in the sarcoplasmic reticulum but also serves to connect the sarcoplasmic reticulum and transverse tubule. Mutations in this gene are associated with malignant hyperthermia susceptibility, central core disease, and minicore myopathy with external ophthalmoplegia. Alternatively spliced transcripts encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

RYR1 Gene-Disease associations (from GenCC):

• malignant hyperthermia, susceptibility to, 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, Ambry Genetics
• congenital multicore myopathy with external ophthalmoplegia

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
• RYR1-related myopathy

  Inheritance: AR, AD Classification: DEFINITIVE Submitted by: ClinGen
• central core myopathy

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
• King-Denborough syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• malignant hyperthermia of anesthesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive centronuclear myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• benign Samaritan congenital myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• congenital myopathy with myasthenic-like onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• lethal multiple pterygium syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in ENST00000359596.8

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000359596.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR1	NM_000540.3	MANE Select	c.11687A>T	p.Asn3896Ile	missense	Exon 84 of 106	NP_000531.2
	RYR1	NM_001042723.2		c.11672A>T	p.Asn3891Ile	missense	Exon 83 of 105	NP_001036188.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR1	ENST00000359596.8	TSL:5 MANE Select	c.11687A>T	p.Asn3896Ile	missense	Exon 84 of 106	ENSP00000352608.2
	RYR1	ENST00000355481.8	TSL:1	c.11672A>T	p.Asn3891Ile	missense	Exon 83 of 105	ENSP00000347667.3
	RYR1	ENST00000594335.6	TSL:1	n.*2397A>T		non_coding_transcript_exon	Exon 81 of 103	ENSP00000470927.2

Frequencies

GnomAD3 genomes AF: 0.0000138 AC: 2 AN: 144722 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000462

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000428 AC: 374 AN: 873454 Hom.: 0 Cov.: 32 AF XY: 0.000383 AC XY: 171 AN XY: 446784

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

African (AFR) AF: 0.000471 AC: 10 AN: 21246

American (AMR) AF: 0.000181 AC: 7 AN: 38746

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 5 AN: 17350

East Asian (EAS) AF: 0.000725 AC: 16 AN: 22080

South Asian (SAS) AF: 0.0000655 AC: 5 AN: 76290

European-Finnish (FIN) AF: 0.000114 AC: 4 AN: 34980

Middle Eastern (MID) AF: 0.000732 AC: 3 AN: 4096

European-Non Finnish (NFE) AF: 0.000491 AC: 306 AN: 623364

Other (OTH) AF: 0.000510 AC: 18 AN: 35302

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000138 AC: 2 AN: 144876 Hom.: 0 Cov.: 31 AF XY: 0.0000142 AC XY: 1 AN XY: 70620

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

African (AFR) AF: 0.00 AC: 0 AN: 40298

American (AMR) AF: 0.00 AC: 0 AN: 14656

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3370

East Asian (EAS) AF: 0.000462 AC: 2 AN: 4326

South Asian (SAS) AF: 0.00 AC: 0 AN: 3978

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9302

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65742

Other (OTH) AF: 0.00 AC: 0 AN: 2056

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Central core myopathy (1)
-	1	-	Congenital multicore myopathy with external ophthalmoplegia (1)
-	1	-	Congenital myopathy with fiber type disproportion (1)
-	1	-	Multiminicore myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Benign	22
DANN	Benign	0.94
DEOGEN2	Pathogenic	0.83	D
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.63	D
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	0.61	N
PhyloP100		2.2
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.43
Sift	Benign	0.030	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.98	D
Vest4		0.80
MutPred		0.60		Loss of disorder (P = 0.0833)
MVP		0.99
MPC		0.78
ClinPred		0.90	D
GERP RS		4.8
PromoterAI		-0.10	Neutral
Varity_R		0.62
gMVP		0.59
Mutation Taster		=17/83	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.12
dbscSNV1_RF	Benign	0.23
SpliceAI score (max)		0.13		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1555793251; hg19: chr19-39028598;