chr14-23417200-G-C

Variant names:

• chr14-23417200-G-C
• rs3729823
• NM_000257.4:c.4472C>G
• MYH7 p.Ser1491Cys

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -11 classification points (ACMG Germline Pathogenicity v2019). PP2BS2BP6_Very_Strong

The NM_000257.4(MYH7):c.4472C>G (p.Ser1491Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0115 (AC=18,642) in the gnomAD database across 1,614,158 control chromosomes, including 156 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.0138. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 7.79). Variant has been reported in ClinVar as Benign/Likely Benign (★★★). This exact variant is curated in the UniProt human variants database as Uncertain Significance.

• Frequency:
  • Genomes: 𝑓 0.0085 (13 hom., cov: 33)
  • Exomes 𝑓: 0.012 (143 hom.)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Benign reviewed by expert panel B:27
• Conservation: PhyloP100: 7.79
• Publications: 24 publications found

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]

MYH7 Gene-Disease associations (from GenCC):

• dilated cardiomyopathy 1S

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Ambry Genetics
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• MYH7-related skeletal myopathy

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
• myopathy, myosin storage, autosomal recessive

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• myopathy, myosin storage, autosomal dominant

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• Ebstein anomaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hyaline body myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• left ventricular noncompaction

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen, G2P
• congenital heart disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

MHRT (HGNC:51291): (myosin heavy chain associated RNA transcript) This gene encodes a spliced long non-coding RNA that may act as a cardioprotective agent in the heart. Based on a study of a similar gene in mouse, the encoded transcript may regulate chromatin remodeling by acting as a decoy to the BRG1 chromatin repressor complex thus preventing it from binding to its genomic targets. Blocking the actions of BRG1 could be crucial in protecting the heart from pathological hypertrophy. [provided by RefSeq, Dec 2014]

Classification according to ACMG Germline Pathogenicity v2019

Specifications for MYH7 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript:

Our verdict: Benign. The variant received -11 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PP2Missense in gene with low missense rate		Missense in gene constrained for missense variation where missense is common disease mechanism (PP2); Missense in a gene constrained for missense variation (gnomAD Z-score: 6.806). ClinVar shows strong pathogenic missense enrichment: 622 P/LP and 50 B/LB missense entries (ratio 12.4×).
	BP6Reputable source reports benign		ClinVar ≥3 stars benign — very strong (BP6); ClinVar submissions overwhelmingly benign (≥10 total, ≥80% B/LB, <10% P/LP) — strong (BP6, count-based); ClinVar germline classification: Benign/Likely Benign, 3 star(s). ClinVar submissions strongly and reliably favor benignity (27/27 total B/LB).
	BS2Observed in healthy adult		≥2 homozygotes in gnomAD — observed in healthy adults (BS2); GnomAD homozygous count = 156.; Very high cumulative gnomAD AC = 18642 (any gene).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000257.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	MYH7 NM_000257.4	MANE Select	c.4472C>G p.Ser1491Cys	missense	Exon 32 of 40	Prot: NP_000248.2 UniProt:
	MYH7 NM_001407004.1		c.4472C>G p.Ser1491Cys	missense	Exon 31 of 39	Prot: NP_001393933.1 UniProt:
	MHRT NR_126491.1		n.652-12G>C	intron	Intron 4 of 5	Prot:

MYH7 NM_000257.4

MANE Select

HGVSc / HGVSpc.4472C>Gp.Ser1491Cys

Exon rankExon 32 of 40

missense

Prot: NP_000248.2UniProt: P12883

MYH7 NM_001407004.1

HGVSc / HGVSpc.4472C>Gp.Ser1491Cys

Exon rankExon 31 of 39

missense

Prot: NP_001393933.1UniProt: P12883

MHRT NR_126491.1

HGVSc / HGVSpn.652-12G>C

Exon rankIntron 4 of 5

intron

Prot:

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	MYH7 ENST00000355349.4	TSL:1MANE Select	c.4472C>G p.Ser1491Cys	missense	Exon 32 of 40	Prot: ENSP00000347507.3 UniProt:
	MYH7 ENST00000858540.1		c.4472C>G p.Ser1491Cys	missense	Exon 32 of 40	Prot: ENSP00000528599.1 UniProt:
	MYH7 ENST00000965955.1		c.4472C>G p.Ser1491Cys	missense	Exon 32 of 40	Prot: ENSP00000636014.1 UniProt:

MYH7 ENST00000355349.4

TSL:1MANE Select

HGVSc / HGVSpc.4472C>Gp.Ser1491Cys

Exon rankExon 32 of 40

missense

Prot: ENSP00000347507.3UniProt: P12883

MYH7 ENST00000858540.1

HGVSc / HGVSpc.4472C>Gp.Ser1491Cys

Exon rankExon 32 of 40

missense

Prot: ENSP00000528599.1UniProt: A0ACI8PLM0

MYH7 ENST00000965955.1

HGVSc / HGVSpc.4472C>Gp.Ser1491Cys

Exon rankExon 32 of 40

missense

Prot: ENSP00000636014.1UniProt: A0ACI8PLM0

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.00854	AC:1299	Hom:13	AN:152148	Cov:33
GnomAD2 exomes	AF: 0.00818	AC:2058	Hom:	AN:251494	Cov:
GnomAD4 exome	AF: 0.0119	AC:17342	Hom:143	AN:1461892	Cov:34
GnomAD4 genome	AF: 0.00854	AC:1300	Hom:13	AN:152266	Cov:33
TOPMed (Bravo)	AF: 0.00927	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0114	AC:1402	Hom:6	AN:122554	Cov:
Local & regional cohorts 10 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.0102	AC:24	Hom:1	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.000197	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 1.00	AC:16	Hom:	AN:16	Cov:
ESP6500 (Exome Variant Server)	AF: 0.00861	AC:112	Hom:	AN:13006	Cov:
GenomeAsia100K	AF: 0.00289	AC:10	Hom:	AN:3478	Cov:
Qatari Genome	AF: 0.00700	AC:12	Hom:	AN:1706	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.0000160	AC:2	Hom:0	AN:122380	Cov:
Turkish Variome	AF: 0.0125	AC:84	Hom:2	AN:6718	Cov:
UK10K	AF: 0.0143	AC:108	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.000112	AC:1	Hom:0	AN:8960	Cov:

Showing 16 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.0119 *	131	11016	0.0115 *	202	17548
BipEx(Bipolar disorder (including schizoaffective))	0.0120	341	28420	0.0129	373	28844
Epi25(Epilepsy)	0.0108	455	41958	0.0123	822	66888
SCHEMA(Schizophrenia)	0.00741	867	116988	0.0117	2153	184320

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	12	not specified (12)
-	-	5	not provided (5)
-	-	4	Hypertrophic cardiomyopathy (4)
-	-	2	Hypertrophic cardiomyopathy 1 (2)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1S (1)
-	-	1	Hypertrophic cardiomyopathy;C0007196:Restrictive cardiomyopathy;C0878544:Cardiomyopathy (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	22
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.74	D
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.99	D
GPN-Star LLR	N/A	-8.7
GPN-Star score	N/A	8.7
LIST_S2	Benign	0.85	D
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.29	T
Mutation Taster	N/A	17/83	disease causing
MutationAssessor	Uncertain	2.6	M
PhyloP100	Pathogenic	7.8
popEVE	Benign	-3.2
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.40
Sift	Benign	0.035	D
Sift4G	Benign	0.16	T
Varity_R	N/A	0.34
VESM-3B	Benign	-7.2

Showing 26 of 26 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs3729823;

hg19: chr14-23886409;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar