17-8475850-C-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_001256012.3(MYH10):c.5978G>C(p.Ser1993Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000229 in 1,614,108 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: 𝑓 0.000059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: MYH10 NM_001256012.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.54

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 -5 ACMG points.

• PP2: Missense variant where missense usually causes diseases, MYH10
• BP4: Computational evidence support a benign effect (MetaRNN=0.08192077).
• BS2: High AC in GnomAd at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH10	NM_001256012.3	c.5978G>C	p.Ser1993Thr	missense_variant	43/43	ENST00000360416.8
MYH10	NM_001375266.1	c.5915G>C	p.Ser1972Thr	missense_variant	42/42
MYH10	NM_001256095.2	c.5912G>C	p.Ser1971Thr	missense_variant	42/42
MYH10	NM_005964.5	c.5885G>C	p.Ser1962Thr	missense_variant	41/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH10	ENST00000360416.8	c.5978G>C	p.Ser1993Thr	missense_variant	43/43	1	NM_001256012.3

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152220 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000199 AC: 5 AN: 251452 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135894

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00

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: 0.0000192 AC: 28 AN: 1461888 Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11 AN XY: 727244

Gnomad4 AFR exome AF: 0.000747

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152220 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74370

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.00

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: 0.0000982

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 06, 2022

The c.5885G>C (p.S1962T) alteration is located in exon 41 (coding exon 40) of the MYH10 gene. This alteration results from a G to C substitution at nucleotide position 5885, causing the serine (S) at amino acid position 1962 to be replaced by a threonine (T). 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	0.063
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.32
Cadd	Uncertain	23
Dann	Benign	0.85
Eigen	Benign	-0.16
Eigen_PC	Benign	0.059
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.72	T;T;T
M_CAP	Benign	0.0081	T
MetaRNN	Benign	0.082	T;T;T
MetaSVM	Benign	-0.58	T
MutationTaster	Benign	0.99	D;D;D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.99	N;.;N
REVEL	Benign	0.28
Sift	Benign	0.75	T;.;T
Sift4G	Benign	0.84	T;T;T
Polyphen		0.0	.;.;B
Vest4		0.16
MVP		0.59
MPC		0.37
ClinPred		0.088	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.26
gMVP		0.31

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: rs149634202; hg19: chr17-8379168;