NM_001145809.2:c.4255C>T

Variant names:

• chr19-50280348-C-T
• rs115019972
• NM_001145809.2:c.4255C>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.4255C>T​(p.Arg1419Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000942 in 1,547,494 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0051 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00049 (7 hom.)
• Consequence: MYH14 NM_001145809.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 4.36
• Publications: 3 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: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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=0.0073207915).
• BP6: Variant 19-50280348-C-T is Benign according to our data. Variant chr19-50280348-C-T is described in ClinVar as Benign. ClinVar VariationId is 164189.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 = 0.00507 (772/152270) while in subpopulation AFR AF = 0.0175 (727/41550). AF 95% confidence interval is 0.0164. There are 6 homozygotes in GnomAd4. There are 364 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 772 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.4255C>T	p.Arg1419Trp	missense	Exon 32 of 43	NP_001139281.1
	MYH14	NM_001077186.2		c.4156C>T	p.Arg1386Trp	missense	Exon 31 of 42	NP_001070654.1
	MYH14	NM_024729.4		c.4132C>T	p.Arg1378Trp	missense	Exon 30 of 41	NP_079005.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH14	ENST00000642316.2	MANE Select	c.4255C>T	p.Arg1419Trp	missense	Exon 32 of 43	ENSP00000493594.1
	MYH14	ENST00000425460.6	TSL:5	c.4156C>T	p.Arg1386Trp	missense	Exon 31 of 42	ENSP00000407879.1
	MYH14	ENST00000598205.5	TSL:5	c.4156C>T	p.Arg1386Trp	missense	Exon 31 of 42	ENSP00000472543.1

Frequencies

GnomAD3 genomes AF: 0.00508 AC: 773 AN: 152152 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0176

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

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: 0.0000294

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.000986 AC: 150 AN: 152134 AF XY: 0.000693

Gnomad AFR exome AF: 0.0152

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000923

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000701

GnomAD4 exome AF: 0.000491 AC: 685 AN: 1395224 Hom.: 7 Cov.: 32 AF XY: 0.000394 AC XY: 271 AN XY: 687778

African (AFR) AF: 0.0175 AC: 552 AN: 31506

American (AMR) AF: 0.00110 AC: 39 AN: 35574

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25062

East Asian (EAS) AF: 0.00 AC: 0 AN: 35680

South Asian (SAS) AF: 0.0000507 AC: 4 AN: 78916

European-Finnish (FIN) AF: 0.0000204 AC: 1 AN: 49052

Middle Eastern (MID) AF: 0.000235 AC: 1 AN: 4254

European-Non Finnish (NFE) AF: 0.0000204 AC: 22 AN: 1077468

Other (OTH) AF: 0.00114 AC: 66 AN: 57712

GnomAD4 genome AF: 0.00507 AC: 772 AN: 152270 Hom.: 6 Cov.: 32 AF XY: 0.00489 AC XY: 364 AN XY: 74444

African (AFR) AF: 0.0175 AC: 727 AN: 41550

American (AMR) AF: 0.00242 AC: 37 AN: 15306

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68010

Other (OTH) AF: 0.00284 AC: 6 AN: 2110

Alfa AF: 0.00118 Hom.: 1

Bravo AF: 0.00545

ESP6500AA AF: 0.0118 AC: 38

ESP6500EA AF: 0.000157 AC: 1

ExAC AF: 0.00116 AC: 35

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D
Eigen	Benign	-0.042
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0073	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	0.69	N
PhyloP100		4.4
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.28
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.17
MVP		0.50
MPC		0.64
ClinPred		0.039	T
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.31
Mutation Taster		=100/0	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: rs115019972; hg19: chr19-50783605; COSMIC: COSV51826375; COSMIC: COSV51826375;