17-8475947-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2 BS2

The NM_001256012.3(MYH10):c.5881C>T(p.Arg1961Trp) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000701 in 1,612,442 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000066 (0 hom.)
• Consequence: MYH10 NM_001256012.3 missense, splice_region
• Scores: Splicing: ADA: 0.3816
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.05

Genes affected

MYH10 (HGNC:7568): (myosin heavy chain 10) This gene encodes a member of the myosin superfamily. The protein represents a conventional non-muscle myosin; it should not be confused with the unconventional myosin-10 (MYO10). Myosins are actin-dependent motor proteins with diverse functions including regulation of cytokinesis, cell motility, and cell polarity. Mutations in this gene have been associated with May-Hegglin anomaly and developmental defects in brain and heart. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]

NDEL1 (HGNC:17620): (nudE neurodevelopment protein 1 like 1) Enables identical protein binding activity. Involved in chromosome segregation; positive regulation of GTPase activity; and regulation of intracellular protein transport. Located in kinetochore. Biomarker of schizophrenia. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PP2: Missense variant where missense usually causes diseases, MYH10
• BS2: High AC in GnomAd at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH10	NM_001256012.3	c.5881C>T	p.Arg1961Trp	missense_variant, splice_region_variant	43/43	ENST00000360416.8
MYH10	NM_001375266.1	c.5818C>T	p.Arg1940Trp	missense_variant, splice_region_variant	42/42
MYH10	NM_001256095.2	c.5815C>T	p.Arg1939Trp	missense_variant, splice_region_variant	42/42
MYH10	NM_005964.5	c.5788C>T	p.Arg1930Trp	missense_variant, splice_region_variant	41/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH10	ENST00000360416.8	c.5881C>T	p.Arg1961Trp	missense_variant, splice_region_variant	43/43	1	NM_001256012.3

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152234 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000108 AC: 27 AN: 249526 Hom.: 0 AF XY: 0.0000889 AC XY: 12 AN XY: 134982

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000524

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: 0.0000265

Gnomad OTH exome AF: 0.000822

GnomAD4 exome AF: 0.0000657 AC: 96 AN: 1460090 Hom.: 0 Cov.: 31 AF XY: 0.0000619 AC XY: 45 AN XY: 726426

Gnomad4 AFR exome AF: 0.0000897

Gnomad4 AMR exome AF: 0.000561

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000761

Gnomad4 NFE exome AF: 0.0000522

Gnomad4 OTH exome AF: 0.0000663

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152352 Hom.: 0 Cov.: 33 AF XY: 0.000134 AC XY: 10 AN XY: 74502

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000619 Hom.: 0

Bravo AF: 0.000166

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000824 AC: 10

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 27, 2023

The c.5788C>T (p.R1930W) alteration is located in exon 41 (coding exon 40) of the MYH10 gene. This alteration results from a C to T substitution at nucleotide position 5788, causing the arginine (R) at amino acid position 1930 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Sep 18, 2022

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Uncertain	0.038	T
BayesDel_noAF	Pathogenic	0.16
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.54	D;D;D
MetaSVM	Uncertain	0.29	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-4.4	D;.;D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0010	D;.;D
Sift4G	Uncertain	0.022	D;D;D
Polyphen		1.0	.;.;D
Vest4		0.56
MVP		0.77
MPC		1.1
ClinPred		0.86	D
GERP RS		3.9
Varity_R		0.50
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.38
dbscSNV1_RF	Benign	0.47
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: rs199834633; hg19: chr17-8379265; COSMIC: COSV52606125; COSMIC: COSV52606125;