rs45503601

Positions:

• chr14-23417017-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000257.4(MYH7):​c.4520-25C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00983 in 1,614,224 control chromosomes in the GnomAD database, including 113 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0078 (5 hom., cov: 33)
  • Exomes 𝑓: 0.010 (108 hom.)
• Consequence: MYH7 NM_000257.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.48

Genes affected

MYH7 (HGNC:7577): (myosin heavy chain 7) Muscle myosin is a hexameric protein containing 2 heavy chain subunits, 2 alkali light chain subunits, and 2 regulatory light chain subunits. This gene encodes the beta (or slow) heavy chain subunit of cardiac myosin. It is expressed predominantly in normal human ventricle. It is also expressed in skeletal muscle tissues rich in slow-twitch type I muscle fibers. Changes in the relative abundance of this protein and the alpha (or fast) heavy subunit of cardiac myosin correlate with the contractile velocity of cardiac muscle. Its expression is also altered during thyroid hormone depletion and hemodynamic overloading. Mutations in this gene are associated with familial hypertrophic cardiomyopathy, myosin storage myopathy, dilated cardiomyopathy, and Laing distal myopathy. [provided by RefSeq, May 2022]

MHRT (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 14-23417017-G-A is Benign according to our data. Variant chr14-23417017-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 188636.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23417017-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00782 (1191/152352) while in subpopulation NFE AF= 0.0124 (841/68042). AF 95% confidence interval is 0.0117. There are 5 homozygotes in gnomad4. There are 543 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH7	NM_000257.4	c.4520-25C>T		intron_variant		ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1	c.4520-25C>T		intron_variant			NP_001393933.1
MHRT	NR_126491.1	n.651+9G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4	c.4520-25C>T		intron_variant		1	NM_000257.4	ENSP00000347507.3

Frequencies

GnomAD3 genomes AF: 0.00783 AC: 1192 AN: 152234 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00232

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00798

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00705

Gnomad FIN AF: 0.00706

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0124

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00728 AC: 1831 AN: 251472 Hom.: 6 AF XY: 0.00748 AC XY: 1017 AN XY: 135908

Gnomad AFR exome AF: 0.00197

Gnomad AMR exome AF: 0.00390

Gnomad ASJ exome AF: 0.00198

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00830

Gnomad FIN exome AF: 0.00578

Gnomad NFE exome AF: 0.0107

Gnomad OTH exome AF: 0.00815

GnomAD4 exome AF: 0.0100 AC: 14677 AN: 1461872 Hom.: 108 Cov.: 34 AF XY: 0.0101 AC XY: 7321 AN XY: 727238

Gnomad4 AFR exome AF: 0.00140

Gnomad4 AMR exome AF: 0.00416

Gnomad4 ASJ exome AF: 0.00283

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00854

Gnomad4 FIN exome AF: 0.00594

Gnomad4 NFE exome AF: 0.0115

Gnomad4 OTH exome AF: 0.00844

GnomAD4 genome AF: 0.00782 AC: 1191 AN: 152352 Hom.: 5 Cov.: 33 AF XY: 0.00729 AC XY: 543 AN XY: 74506

Gnomad4 AFR AF: 0.00231

Gnomad4 AMR AF: 0.00790

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00726

Gnomad4 FIN AF: 0.00706

Gnomad4 NFE AF: 0.0124

Gnomad4 OTH AF: 0.00614

Alfa AF: 0.00816 Hom.: 1

Bravo AF: 0.00729

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	MYH7: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2018	This variant is associated with the following publications: (PMID: 15483641) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Congenital myopathy with fiber type disproportion;C1834481:Dilated cardiomyopathy 1S;C1842160:Myosin storage myopathy;C1850709:Myopathy, myosin storage, autosomal recessive;C3495498:Hypertrophic cardiomyopathy 1;C4552004:MYH7-related skeletal myopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 05, 2021

- -

Hypertrophic cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 15, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.8
DANN	Benign	0.57

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: rs45503601; hg19: chr14-23886226;