17-10445287-C-A

Position:

• chr17-10445287-C-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_017533.2(MYH4):​c.5245G>T​(p.Val1749Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: MYH4 NM_017533.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.101

Genes affected

MYH4 (HGNC:7574): (myosin heavy chain 4) Enables double-stranded RNA binding activity. Involved in muscle contraction. Located in myofibril. [provided by Alliance of Genome Resources, Apr 2022]

(HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.28537297).
• BS2: High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH4	NM_017533.2	c.5245G>T	p.Val1749Phe	missense_variant	36/40	ENST00000255381.2
MYHAS	NR_125367.1	n.167+39049C>A		intron_variant, non_coding_transcript_variant
MYH4	XM_017024676.2	c.5245G>T	p.Val1749Phe	missense_variant	34/38

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH4	ENST00000255381.2	c.5245G>T	p.Val1749Phe	missense_variant	36/40	1	NM_017533.2	P1
	ENST00000399342.6	n.206+39010C>A		intron_variant, non_coding_transcript_variant		3
	ENST00000581304.1	n.143+39049C>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461846 Hom.: 0 Cov.: 41 AF XY: 0.00000550 AC XY: 4 AN XY: 727226

Gnomad4 AFR exome AF: 0.000119

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: 0.00

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2022

The c.5245G>T (p.V1749F) alteration is located in exon 36 (coding exon 34) of the MYH4 gene. This alteration results from a G to T substitution at nucleotide position 5245, causing the valine (V) at amino acid position 1749 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	0.0082	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.45	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.29	N
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.46	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	0.97	N
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.12	T
Polyphen		0.29	B
Vest4		0.32
MutPred		0.66		Loss of helix (P = 0.2271);
MVP		0.72
MPC		0.38
ClinPred		0.93	D
GERP RS		3.6
Varity_R		0.065
gMVP		0.34

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: rs144889690; hg19: chr17-10348604;