rs200485394

Variant names:

• chr19-50307053-C-T
• rs200485394
• NM_001145809.2:c.5683C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001145809.2(MYH14):​c.5683C>T​(p.Arg1895Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000257 in 1,547,754 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00058 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: MYH14 NM_001145809.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.63
• Publications: 7 publications found

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]

MYH14 Gene-Disease associations (from GenCC):

• autosomal dominant nonsyndromic hearing loss 4A

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• peripheral neuropathy-myopathy-hoarseness-hearing loss syndrome

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.043082774).
• BP6: Variant 19-50307053-C-T is Benign according to our data. Variant chr19-50307053-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 504622.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000578 (88/152340) while in subpopulation AFR AF = 0.00178 (74/41572). AF 95% confidence interval is 0.00145. There are 0 homozygotes in GnomAd4. There are 36 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 88 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001145809.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH14	NM_001145809.2	MANE Select	c.5683C>T	p.Arg1895Cys	missense	Exon 41 of 43	NP_001139281.1	Q7Z406-2
	MYH14	NM_001077186.2		c.5584C>T	p.Arg1862Cys	missense	Exon 40 of 42	NP_001070654.1	Q7Z406-6
	MYH14	NM_024729.4		c.5560C>T	p.Arg1854Cys	missense	Exon 39 of 41	NP_079005.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH14	ENST00000642316.2	MANE Select	c.5683C>T	p.Arg1895Cys	missense	Exon 41 of 43	ENSP00000493594.1	Q7Z406-2
	MYH14	ENST00000425460.6	TSL:5	c.5584C>T	p.Arg1862Cys	missense	Exon 40 of 42	ENSP00000407879.1	Q7Z406-6
	MYH14	ENST00000598205.5	TSL:5	c.5584C>T	p.Arg1862Cys	missense	Exon 40 of 42	ENSP00000472543.1	Q7Z406-6

Frequencies

GnomAD3 genomes AF: 0.000578 AC: 88 AN: 152222 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00179

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000304 AC: 47 AN: 154470 AF XY: 0.000282

Gnomad AFR exome AF: 0.00263

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000232

Gnomad OTH exome AF: 0.000460

GnomAD4 exome AF: 0.000222 AC: 310 AN: 1395414 Hom.: 0 Cov.: 30 AF XY: 0.000216 AC XY: 149 AN XY: 688360

African (AFR) AF: 0.00235 AC: 74 AN: 31526

American (AMR) AF: 0.000420 AC: 15 AN: 35678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25142

East Asian (EAS) AF: 0.00 AC: 0 AN: 35714

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79166

European-Finnish (FIN) AF: 0.0000205 AC: 1 AN: 48744

Middle Eastern (MID) AF: 0.000881 AC: 5 AN: 5674

European-Non Finnish (NFE) AF: 0.000179 AC: 193 AN: 1075860

Other (OTH) AF: 0.000363 AC: 21 AN: 57910

GnomAD4 genome AF: 0.000578 AC: 88 AN: 152340 Hom.: 0 Cov.: 32 AF XY: 0.000483 AC XY: 36 AN XY: 74508

African (AFR) AF: 0.00178 AC: 74 AN: 41572

American (AMR) AF: 0.000261 AC: 4 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000258 Hom.: 0

Bravo AF: 0.000888

ESP6500AA AF: 0.00149 AC: 5

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000175 AC: 7

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.75	D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.043	T
MetaSVM	Uncertain	0.38	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		2.6
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-6.8	D
REVEL	Pathogenic	0.67
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.012	D
Polyphen		1.0	D
Vest4		0.53
MVP		0.72
MPC		0.76
ClinPred		0.11	T
GERP RS		4.4
Varity_R		0.19
gMVP		0.40
Mutation Taster		=63/37	polymorphism

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

Other links and lift over

dbSNP: rs200485394; hg19: chr19-50810310; COSMIC: COSV51816739; COSMIC: COSV51816739;