19-50261508-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PP3_ModerateBS1_SupportingBS2

The NM_001145809.2(MYH14):c.2458C>T(p.Arg820Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000605 in 1,554,252 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R820S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000048 ( 0 hom., cov: 17)

Exomes 𝑓: 0.000062 ( 0 hom. )

Consequence

MYH14
NM_001145809.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 3.88

Publications

0 publications found

Variant links:

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

MYH14 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.847

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000616 (88/1429334) while in subpopulation MID AF = 0.000176 (1/5684). AF 95% confidence interval is 0.000057. There are 0 homozygotes in GnomAdExome4. There are 56 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 6 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MYH14	NM_001145809.2	MANE Select	c.2458C>T	p.Arg820Cys	missense	Exon 21 of 43	NP_001139281.1
MYH14	NM_001077186.2		c.2359C>T	p.Arg787Cys	missense	Exon 20 of 42	NP_001070654.1
MYH14	NM_024729.4		c.2335C>T	p.Arg779Cys	missense	Exon 19 of 41	NP_079005.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MYH14	ENST00000642316.2	MANE Select	c.2458C>T	p.Arg820Cys	missense	Exon 21 of 43	ENSP00000493594.1
MYH14	ENST00000599920.5	TSL:1	c.2359C>T	p.Arg787Cys	missense	Exon 20 of 24	ENSP00000469573.1
MYH14	ENST00000425460.6	TSL:5	c.2359C>T	p.Arg787Cys	missense	Exon 20 of 42	ENSP00000407879.1

Frequencies

GnomAD3 genomes

AF:

0.0000480

AC:

AN:

124918

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.000100

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000567

AC:

AN:

229392

AF XY:

0.0000717

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000477

Gnomad NFE exome

AF:

0.000114

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000616

AC:

AN:

1429334

Hom.:

Cov.:

AF XY:

0.0000789

AC XY:

AN XY:

710118

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31534

American (AMR)

AF:

0.0000482

AC:

AN:

41452

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25412

East Asian (EAS)

AF:

0.00

AC:

AN:

36034

South Asian (SAS)

AF:

0.00

AC:

AN:

81222

European-Finnish (FIN)

AF:

0.0000581

AC:

AN:

51662

Middle Eastern (MID)

AF:

0.000176

AC:

AN:

5684

European-Non Finnish (NFE)

AF:

0.0000702

AC:

AN:

1097184

Other (OTH)

AF:

0.0000845

AC:

AN:

59150

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000480

AC:

AN:

124918

Hom.:

Cov.:

AF XY:

0.0000671

AC XY:

AN XY:

59606

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31338

American (AMR)

AF:

0.00

AC:

AN:

11910

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3126

East Asian (EAS)

AF:

0.00

AC:

AN:

4242

South Asian (SAS)

AF:

0.00

AC:

AN:

3318

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8442

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000100

AC:

AN:

59856

Other (OTH)

AF:

0.00

AC:

AN:

1620

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000130

Hom.:

ExAC

AF:

0.0000496

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (2)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.60

BayesDel_addAF

Uncertain

0.062

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.80

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.94

M_CAP

Uncertain

0.18

MetaRNN

Pathogenic

0.85

MetaSVM

Uncertain

0.73

MutationAssessor

Uncertain

2.2

PhyloP100

3.9

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-7.8

REVEL

Pathogenic

0.65

Sift

Benign

0.032

Sift4G

Uncertain

0.028

Polyphen

1.0

Vest4

0.82

MutPred

0.66

Loss of MoRF binding (P = 0.0556)

MVP

0.86

MPC

1.6

ClinPred

0.63

GERP RS

4.5

Varity_R

0.40

gMVP

0.90

Mutation Taster

=19/81

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over