20-34977660-T-A

Variant summary

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

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0160

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=0.1322769).
• BS2: High AC in GnomAd at 10 AD gene.

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7B	ENST00000262873.13	c.-93T>A		5_prime_UTR_variant	4/45	1	NM_020884.7	P1
MYH7B	ENST00000673749.1	n.442T>A		non_coding_transcript_exon_variant	4/9
MYH7B	ENST00000470929.5			upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.0000705 AC: 10 AN: 141784 Hom.: 0 Cov.: 29

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: 7 AN: 203686 Hom.: 0 AF XY: 0.0000367 AC XY: 4 AN XY: 109074

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: 31 AN: 1364798 Hom.: 0 Cov.: 31 AF XY: 0.0000222 AC XY: 15 AN XY: 675038

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: 10 AN: 141854 Hom.: 0 Cov.: 29 AF XY: 0.0000292 AC XY: 2 AN XY: 68594

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.: 0

ExAC AF: 0.0000251 AC: 3

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

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	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	15
Dann	Benign	0.79
Eigen	Benign	-0.032
Eigen_PC	Benign	-0.029
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.40	T;T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-0.39	T
MutationTaster	Benign	0.99	N
PrimateAI	Benign	0.32	T
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	T
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

Other links and lift over

dbSNP: rs762744206; hg19: chr20-33565463;