chr20-34977660-T-A

Position:

chr20-34977660-T-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_020884.7(MYH7B):c.-93T>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000272 in 1,506,652 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000070 ( 0 hom., cov: 29)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

MYH7B
NM_020884.7 5_prime_UTR

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.0160

Variant links:

Genes affected

MYH7B (HGNC:15906): (myosin heavy chain 7B) The myosin II molecule is a multi-subunit complex consisting of two heavy chains and four light chains. This gene encodes a heavy chain of myosin II, which is a member of the motor-domain superfamily. The heavy chain includes a globular motor domain, which catalyzes ATP hydrolysis and interacts with actin, and a tail domain in which heptad repeat sequences promote dimerization by interacting to form a rod-like alpha-helical coiled coil. This heavy chain subunit is a slow-twitch myosin. Alternatively spliced transcript variants have been found, but the full-length nature of these variants is not determined. [provided by RefSeq, Mar 2010]

MYH7B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1322769).

BS2

High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH7B	NM_020884.7 link	c.-93T>A		5_prime_UTR_variant	4/45	ENST00000262873.13	NP_065935.4	A7E2Y1

Ensembl

Gene	Transcript	HGVSc	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MYH7B	ENST00000262873 link	c.-93T>A	5_prime_UTR_variant	4/45	1	NM_020884.7	ENSP00000262873.8	A0A6E1W127
MYH7B	ENST00000673749.1 link	n.442T>A	non_coding_transcript_exon_variant	4/9
MYH7B	ENST00000470929.5 link	n.-7T>A	upstream_gene_variant		2

Frequencies

GnomAD3 genomes

AF:

0.0000705

AC:

AN:

141784

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000752

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00342

Gnomad NFE

AF:

0.000107

Gnomad OTH

AF:

0.000501

GnomAD3 exomes

AF:

0.0000344

AC:

AN:

203686

Hom.:

AF XY:

0.0000367

AC XY:

AN XY:

109074

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000347

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:

0.0000664

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000227

AC:

AN:

1364798

Hom.:

Cov.:

AF XY:

0.0000222

AC XY:

AN XY:

675038

show subpopulations

Gnomad4 AFR exome

AF:

0.0000322

Gnomad4 AMR exome

AF:

0.0000267

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:

0.0000228

Gnomad4 OTH exome

AF:

0.0000729

GnomAD4 genome

AF:

0.0000705

AC:

AN:

141854

Hom.:

Cov.:

AF XY:

0.0000292

AC XY:

AN XY:

68594

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000751

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000107

Gnomad4 OTH

AF:

0.000496

Alfa

AF:

0.000118

Hom.:

ExAC

AF:

0.0000251

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 17, 2024

Variant summary: MYH7B c.-93T>A is located in the untranslated mRNA region upstream of the initiation codon. The variant allele was found at a frequency of 3.4e-05 in 203686 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.-93T>A in individuals affected with MYH7B-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 2183935). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 04, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant has not been reported in the literature in individuals affected with MYH7B-related conditions. This variant is present in population databases (rs762744206, gnomAD 0.008%). This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 12 of the MYH7B protein (p.Cys12Ser). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Benign

0.79

Eigen

Benign

-0.032

Eigen_PC

Benign

-0.029

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.40

T;T

M_CAP

Benign

0.034

MetaRNN

Benign

0.13

T;T

MetaSVM

Benign

-0.39

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.080

N;.

REVEL

Benign

0.16

Sift

Pathogenic

0.0

D;.

Vest4

0.11

MutPred

0.24

Gain of disorder (P = 0.0089);.;

MVP

0.56

MPC

0.18

ClinPred

0.052

GERP RS

1.4

Varity_R

0.11

gMVP

0.58

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

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