Genetic Variant MYBPH:p.Gly311Glu (chr1-203171062-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004997.3(MYBPH):c.932G>A(p.Gly311Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000568 in 1,585,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000049 ( 0 hom. )

Consequence

MYBPH
NM_004997.3 missense, splice_region

Scores

Splicing: ADA: 0.001028

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.759

Variant links:

Genes affected

MYBPH (HGNC:7552): (myosin binding protein H) Predicted to be a structural constituent of muscle. Predicted to be involved in regulation of striated muscle contraction. Predicted to be located in myosin filament. [provided by Alliance of Genome Resources, Apr 2022]

MYBPH links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07865569).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPH	NM_004997.3 link	c.932G>A	p.Gly311Glu	missense_variant, splice_region_variant	Exon 6 of 11	ENST00000255416.9	NP_004988.2	Q13203
MYBPH	XM_047421205.1 link	c.1055G>A	p.Gly352Glu	missense_variant, splice_region_variant	Exon 7 of 12		XP_047277161.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPH	ENST00000255416.9 link	c.932G>A	p.Gly311Glu	missense_variant, splice_region_variant	Exon 6 of 11	1	NM_004997.3	ENSP00000255416.4		Q13203

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152252

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

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

GnomAD3 exomes

AF:

0.0000310

AC:

AN:

225902

Hom.:

AF XY:

0.0000164

AC XY:

AN XY:

121962

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000240

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000488

AC:

AN:

1433622

Hom.:

Cov.:

AF XY:

0.00000422

AC XY:

AN XY:

711666

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000180

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152252

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74390

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.932G>A (p.G311E) alteration is located in exon 6 (coding exon 6) of the MYBPH gene. This alteration results from a G to A substitution at nucleotide position 932, causing the glycine (G) at amino acid position 311 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.50

CADD

Uncertain

DANN

Benign

0.97

DEOGEN2

Benign

0.086

T;T

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.33

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.81

T;T

M_CAP

Benign

0.021

MetaRNN

Benign

0.079

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

.;L

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-2.1

.;N

REVEL

Benign

0.10

Sift

Benign

0.69

.;T

Sift4G

Benign

0.83

T;T

Polyphen

0.044

.;B

Vest4

0.16

MutPred

0.63

Gain of catalytic residue at W313 (P = 0.0571);Gain of catalytic residue at W313 (P = 0.0571);

MVP

0.68

MPC

0.26

ClinPred

0.24

GERP RS

3.9

Varity_R

0.25

gMVP

0.70

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0010

dbscSNV1_RF

Benign

0.11

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over