20-34977669-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_020884.7(MYH7B):c.-84C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000247 in 1,376,236 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 0.00010 (0 hom., cov: 28)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: MYH7B NM_020884.7 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.202

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 Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09736079).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000104 (13/125490) while in subpopulation AMR AF= 0.000675 (7/10364). AF 95% confidence interval is 0.000316. There are 0 homozygotes in gnomad4. There are 10 alleles in male gnomad4 subpopulation. Median coverage is 28. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH7B	NM_020884.7	c.-84C>T		5_prime_UTR_variant	4/45	ENST00000262873.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7B	ENST00000262873.13	c.-84C>T		5_prime_UTR_variant	4/45	1	NM_020884.7	P1
MYH7B	ENST00000470929.5	n.3C>T		non_coding_transcript_exon_variant	1/6	2
MYH7B	ENST00000673749.1	n.451C>T		non_coding_transcript_exon_variant	4/9

Frequencies

GnomAD3 genomes AF: 0.000104 AC: 13 AN: 125490 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.000180

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000675

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: 0.0000503 AC: 10 AN: 198716 Hom.: 0 AF XY: 0.0000659 AC XY: 7 AN XY: 106258

Gnomad AFR exome AF: 0.0000869

Gnomad AMR exome AF: 0.000319

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: 0.0000168 AC: 21 AN: 1250746 Hom.: 0 Cov.: 32 AF XY: 0.0000227 AC XY: 14 AN XY: 616830

Gnomad4 AFR exome AF: 0.000107

Gnomad4 AMR exome AF: 0.000267

Gnomad4 ASJ exome AF: 0.0000533

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000713

Gnomad4 OTH exome AF: 0.0000211

GnomAD4 genome AF: 0.000104 AC: 13 AN: 125490 Hom.: 0 Cov.: 28 AF XY: 0.000169 AC XY: 10 AN XY: 59112

Gnomad4 AFR AF: 0.000180

Gnomad4 AMR AF: 0.000675

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: 0.0000793

ExAC AF: 0.00000840 AC: 1

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

Apr 01, 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: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0". The cysteine 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. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 15 of the MYH7B protein (p.Arg15Cys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	13
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.68	D;.
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.58	T;T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.097	T;T
MetaSVM	Uncertain	-0.19	T
MutationTaster	Benign	0.92	N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.18	N;.
REVEL	Benign	0.16
Sift	Uncertain	0.017	D;.
Vest4		0.19
MutPred		0.35		Loss of MoRF binding (P = 0.0077);.;
MVP		0.57
MPC		0.64
ClinPred		0.15	T
GERP RS		0.60
Varity_R		0.10
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs774018469; hg19: chr20-33565472;