17-10492430-T-C

Position:

• chr17-10492430-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM2 BP4_Strong BS2

The NM_005963.4(MYH1):​c.5806A>G​(p.Ile1936Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,572 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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: 0.0000034 (0 hom.)
• Consequence: MYH1 NM_005963.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.979

Genes affected

MYH1 (HGNC:7567): (myosin heavy chain 1) Myosin is a major contractile protein which converts chemical energy into mechanical energy through the hydrolysis of ATP. Myosin is a hexameric protein composed of a pair of myosin heavy chains (MYH) and two pairs of nonidentical light chains. Myosin heavy chains are encoded by a multigene family. In mammals at least 10 different myosin heavy chain (MYH) isoforms have been described from striated, smooth, and nonmuscle cells. These isoforms show expression that is spatially and temporally regulated during development. [provided by RefSeq, Jul 2008]

(HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05409527).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH1	NM_005963.4	c.5806A>G	p.Ile1936Val	missense_variant	40/40	ENST00000226207.6	NP_005954.3
MYHAS	NR_125367.1	n.168-75107T>C		intron_variant, non_coding_transcript_variant
MYH1	XM_017024675.2	c.5806A>G	p.Ile1936Val	missense_variant	40/40		XP_016880164.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH1	ENST00000226207.6	c.5806A>G	p.Ile1936Val	missense_variant	40/40	5	NM_005963.4	ENSP00000226207	P1
	ENST00000399342.6	n.207-40894T>C		intron_variant, non_coding_transcript_variant		3
	ENST00000581304.1	n.144-40894T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461572 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 727078

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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

Dec 20, 2023

The c.5806A>G (p.I1936V) alteration is located in exon 40 (coding exon 38) of the MYH1 gene. This alteration results from a A to G substitution at nucleotide position 5806, causing the isoleucine (I) at amino acid position 1936 to be replaced by a valine (V). 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	0.076
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	17
DANN	Uncertain	0.97
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.054	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.69	N
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.040	N
REVEL	Benign	0.23
Sift	Benign	0.36	T
Sift4G	Benign	0.35	T
Polyphen		0.0	B
Vest4		0.12
MutPred		0.073		Gain of MoRF binding (P = 0.0893);
MVP		0.56
MPC		0.076
ClinPred		0.11	T
GERP RS		4.6
Varity_R		0.053
gMVP		0.061

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-10395747;