Genetic Variant MYBPH:p.Ala114Asp (chr1-203174597-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004997.3(MYBPH):c.341C>A(p.Ala114Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,443,348 control chromosomes in the GnomAD database, with no homozygous occurrence. 17/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

MYBPH
NM_004997.3 missense, splice_region

Scores

Splicing: ADA: 0.0003175

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.31

Publications

16 publications found

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 was made for transcript

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

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPH	NM_004997.3 link	c.341C>A	p.Ala114Asp	missense_variant, splice_region_variant	Exon 3 of 11	ENST00000255416.9	NP_004988.2
MYBPH	XM_047421205.1 link	c.464C>A	p.Ala155Asp	missense_variant, splice_region_variant	Exon 4 of 12		XP_047277161.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPH	ENST00000255416.9 link	c.341C>A	p.Ala114Asp	missense_variant, splice_region_variant	Exon 3 of 11	1	NM_004997.3	ENSP00000255416.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

241992

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

6.93e-7

AC:

AN:

1443348

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

714918

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

33144

American (AMR)

AF:

0.00

AC:

AN:

43908

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25814

East Asian (EAS)

AF:

0.00

AC:

AN:

39164

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85396

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53022

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5682

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1097858

Other (OTH)

AF:

0.00

AC:

AN:

59360

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.023

T;T

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.24

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.52

T;T

M_CAP

Benign

0.013

MetaRNN

Uncertain

0.56

D;D

MetaSVM

Benign

-0.78

MutationAssessor

Benign

0.0

.;L

PhyloP100

1.3

PrimateAI

Uncertain

0.50

PROVEAN

Benign

0.0

.;N

REVEL

Benign

0.0

Sift

Pathogenic

0.0

.;T

Sift4G

Benign

0.16

T;T

Vest4

0.31

ClinPred

0.34

GERP RS

4.6

Varity_R

0.19

gMVP

0.37

Mutation Taster

=68/32

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00032

dbscSNV1_RF

Benign

0.038

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over