Genetic Variant NM_001145809.2:c.2900C>T (chr19-50268234-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001145809.2(MYH14):c.2900C>T(p.Thr967Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000377 in 1,563,796 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T967R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000039 ( 0 hom. )

Consequence

MYH14
NM_001145809.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 1.74

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: 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

MYH14 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03975004).

BP6

Variant 19-50268234-C-T is Benign according to our data. Variant chr19-50268234-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 893919.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000263 (4/152276) while in subpopulation EAS AF = 0.000388 (2/5160). AF 95% confidence interval is 0.0000686. There are 0 homozygotes in GnomAd4. There are 2 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAdExome4 at 55 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	UniProt
MYH14	NM_001145809.2	MANE Select	c.2900C>T	p.Thr967Met	missense	Exon 24 of 43	NP_001139281.1	Q7Z406-2
MYH14	NM_001077186.2		c.2801C>T	p.Thr934Met	missense	Exon 23 of 42	NP_001070654.1	Q7Z406-6
MYH14	NM_024729.4		c.2777C>T	p.Thr926Met	missense	Exon 22 of 41	NP_079005.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MYH14	ENST00000642316.2	MANE Select	c.2900C>T	p.Thr967Met	missense	Exon 24 of 43	ENSP00000493594.1	Q7Z406-2
MYH14	ENST00000599920.5	TSL:1	c.2801C>T	p.Thr934Met	missense	Exon 23 of 24	ENSP00000469573.1	M0QY43
MYH14	ENST00000425460.6	TSL:5	c.2801C>T	p.Thr934Met	missense	Exon 23 of 42	ENSP00000407879.1	Q7Z406-6

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000387

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

GnomAD2 exomes

AF:

0.0000573

AC:

AN:

174596

AF XY:

0.0000643

show subpopulations

Gnomad AFR exome

AF:

0.000108

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000570

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000273

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000390

AC:

AN:

1411520

Hom.:

Cov.:

AF XY:

0.0000416

AC XY:

AN XY:

697802

show subpopulations

African (AFR)

AF:

0.0000624

AC:

AN:

32036

American (AMR)

AF:

0.00

AC:

AN:

37336

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25248

East Asian (EAS)

AF:

0.000602

AC:

AN:

36560

South Asian (SAS)

AF:

0.0000125

AC:

AN:

79988

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49890

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5104

European-Non Finnish (NFE)

AF:

0.0000267

AC:

AN:

1086788

Other (OTH)

AF:

0.0000171

AC:

AN:

58570

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

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:

0.0000263

AC:

AN:

152276

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41578

American (AMR)

AF:

0.00

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000388

AC:

AN:

5160

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68012

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.588

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:

0.0000231

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000337

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Autosomal dominant nonsyndromic hearing loss 4A (1)

not provided (1)

Peripheral neuropathy-myopathy-hoarseness-hearing loss syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.10

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.51

FATHMM_MKL

Benign

0.44

LIST_S2

Benign

0.85

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.040

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-0.59

PhyloP100

1.7

PrimateAI

Uncertain

0.63

PROVEAN

Benign

2.4

REVEL

Benign

0.13

Sift

Benign

1.0

Sift4G

Benign

0.33

Polyphen

0.050

Vest4

0.13

MVP

0.31

MPC

0.48

ClinPred

0.025

GERP RS

2.7

Varity_R

0.022

gMVP

0.15

Mutation Taster

=77/23

polymorphism

(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