20-34979419-C-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_020884.7(MYH7B):c.121C>G(p.Gln41Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000204 in 1,613,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: MYH7B NM_020884.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.82

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.118472934).
• BS2: High AC in GnomAd at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH7B	NM_020884.7	c.121C>G	p.Gln41Glu	missense_variant	6/45	ENST00000262873.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7B	ENST00000262873.13	c.121C>G	p.Gln41Glu	missense_variant	6/45	1	NM_020884.7	P1
MYH7B	ENST00000470929.5	n.207C>G		non_coding_transcript_exon_variant	3/6	2
MYH7B	ENST00000673749.1	n.655C>G		non_coding_transcript_exon_variant	6/9

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152218 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000121 AC: 3 AN: 248844 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135018

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000185 AC: 27 AN: 1461488 Hom.: 0 Cov.: 32 AF XY: 0.0000234 AC XY: 17 AN XY: 727016

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

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: 0.0000189

Gnomad4 OTH exome AF: 0.0000663

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152336 Hom.: 0 Cov.: 32 AF XY: 0.0000268 AC XY: 2 AN XY: 74490

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000847 Hom.: 0

Bravo AF: 0.0000567

ExAC AF: 0.00000827 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 05, 2023

This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 83 of the MYH7B protein (p.Gln83Glu). This variant is present in population databases (rs200981858, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with MYH7B-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MYH7B protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.37
Cadd	Uncertain	23
Dann	Uncertain	0.98
Eigen	Benign	-0.21
Eigen_PC	Benign	0.011
FATHMM_MKL	Benign	0.66	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-0.77	T
MutationTaster	Benign	0.72	N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.20	N;.
REVEL	Benign	0.13
Sift	Benign	0.18	T;.
Sift4G	Benign	0.45	T;T
Vest4		0.43
MVP		0.57
MPC		0.17
ClinPred		0.11	T
GERP RS		4.9
Varity_R		0.13
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs200981858; hg19: chr20-33567222;