rs397516629

chr19-50272568-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_001145809.2(MYH14):c.3304C>T(p.Arg1102Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000111 in 1,572,110 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: MYH14 NM_001145809.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: -0.134

Genes affected

MYH14 (HGNC:23212): (myosin heavy chain 14) 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-14 (MYO14). Myosins are actin-dependent motor proteins with diverse functions including regulation of cytokinesis, cell motility, and cell polarity. Mutations in this gene result in one form of autosomal dominant hearing impairment. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07359651).
• BP6: Variant 19-50272568-C-T is Benign according to our data. Variant chr19-50272568-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44064.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.
• BS2: High AC in GnomAd at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH14	NM_001145809.2	c.3304C>T	p.Arg1102Trp	missense_variant	27/43	ENST00000642316.2
MYH14	NM_001077186.2	c.3205C>T	p.Arg1069Trp	missense_variant	26/42
MYH14	NM_024729.4	c.3181C>T	p.Arg1061Trp	missense_variant	25/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH14	ENST00000642316.2	c.3304C>T	p.Arg1102Trp	missense_variant	27/43		NM_001145809.2

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152110 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000146 AC: 27 AN: 184702 Hom.: 0 AF XY: 0.000121 AC XY: 12 AN XY: 99068

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000371

Gnomad ASJ exome AF: 0.000112

Gnomad EAS exome AF: 0.000725

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000190

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000112 AC: 159 AN: 1420000 Hom.: 0 Cov.: 32 AF XY: 0.000103 AC XY: 72 AN XY: 702244

Gnomad4 AFR exome AF: 0.0000611

Gnomad4 AMR exome AF: 0.0000265

Gnomad4 ASJ exome AF: 0.0000394

Gnomad4 EAS exome AF: 0.000238

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000594

Gnomad4 NFE exome AF: 0.000127

Gnomad4 OTH exome AF: 0.0000340

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152110 Hom.: 0 Cov.: 31 AF XY: 0.0000807 AC XY: 6 AN XY: 74304

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000208 Hom.: 0

Bravo AF: 0.0000869

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ExAC AF: 0.000110 AC: 13

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 02, 2013

The Arg1102Trp variant in MYH14 has not been reported in the literature nor prev iously identified by our laboratory. Computational analyses (biochemical amino a cid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide str ong support for or against an impact to the protein. Additional data is needed t o determine the clinical significance of this variant. -

Autosomal dominant nonsyndromic hearing loss 4A;C3280556:Peripheral neuropathy-myopathy-hoarseness-hearing loss syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 22, 2022

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 10, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.26
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Benign	-0.00048
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.33	N
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.074	T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.20	T
MutationTaster	Benign	0.99	N;N;N;N
PrimateAI	Uncertain	0.49	T
Sift4G	Uncertain	0.0020	D;D;D;.;D;D;D
Polyphen		1.0	D;D;D;D;D;D;.
Vest4		0.40
MutPred		0.36		.;.;Loss of MoRF binding (P = 0.0921);.;.;Loss of MoRF binding (P = 0.0921);.;
MVP		0.63
MPC		0.59
ClinPred		0.27	T
GERP RS		2.0
Varity_R		0.13
gMVP		0.29

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: rs397516629; hg19: chr19-50775825; COSMIC: COSV51825622; COSMIC: COSV51825622;