Genetic Variant MYH14:p.Pro231Pro (chr19-50223349-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_001145809.2(MYH14):c.693C>T(p.Pro231Pro) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000844 in 1,563,996 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000084 ( 0 hom. )

Consequence

MYH14
NM_001145809.2 splice_region, synonymous

Scores

Splicing: ADA: 0.0002260

Clinical Significance

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

Conservation

PhyloP100: -0.533

Publications

3 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.53).

BP6

Variant 19-50223349-C-T is Benign according to our data. Variant chr19-50223349-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 505603.

BP7

Synonymous conserved (PhyloP=-0.533 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000854 (13/152238) while in subpopulation SAS AF = 0.000207 (1/4832). AF 95% confidence interval is 0.000068. There are 0 homozygotes in GnomAd4. There are 7 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 13 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.693C>T	p.Pro231Pro	splice_region synonymous	Exon 5 of 43	NP_001139281.1
MYH14	NM_001077186.2		c.693C>T	p.Pro231Pro	splice_region synonymous	Exon 5 of 42	NP_001070654.1
MYH14	NM_024729.4		c.693C>T	p.Pro231Pro	splice_region synonymous	Exon 5 of 41	NP_079005.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MYH14	ENST00000642316.2	MANE Select	c.693C>T	p.Pro231Pro	splice_region synonymous	Exon 5 of 43	ENSP00000493594.1
MYH14	ENST00000599920.5	TSL:1	c.693C>T	p.Pro231Pro	splice_region synonymous	Exon 5 of 24	ENSP00000469573.1
MYH14	ENST00000425460.6	TSL:5	c.693C>T	p.Pro231Pro	splice_region synonymous	Exon 5 of 42	ENSP00000407879.1

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.0000925

AC:

AN:

172986

AF XY:

0.000130

show subpopulations

Gnomad AFR exome

AF:

0.000214

Gnomad AMR exome

AF:

0.0000778

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000127

Gnomad OTH exome

AF:

0.000209

GnomAD4 exome

AF:

0.0000843

AC:

119

AN:

1411758

Hom.:

Cov.:

AF XY:

0.0000773

AC XY:

AN XY:

698150

show subpopulations

African (AFR)

AF:

0.0000623

AC:

AN:

32112

American (AMR)

AF:

0.0000812

AC:

AN:

36962

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25312

East Asian (EAS)

AF:

0.00

AC:

AN:

36478

South Asian (SAS)

AF:

0.0000866

AC:

AN:

80816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50146

Middle Eastern (MID)

AF:

0.000175

AC:

AN:

5710

European-Non Finnish (NFE)

AF:

0.0000921

AC:

100

AN:

1085622

Other (OTH)

AF:

0.000102

AC:

AN:

58600

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

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:

0.0000854

AC:

AN:

152238

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41464

American (AMR)

AF:

0.0000654

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.000207

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68044

Other (OTH)

AF:

0.000957

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.521

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:

0.0000447

Hom.:

Bravo

AF:

0.0000756

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

CADD

Benign

2.5

(source)

DANN

Benign

0.65

PhyloP100

-0.53

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00023

dbscSNV1_RF

Benign

0.064

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

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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