NM_001145809.2:c.5533C>T

Variant names:

• chr19-50301724-C-T
• rs199600574
• NM_001145809.2:c.5533C>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.5533C>T​(p.Arg1845Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,613,852 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1845P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0021 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00093 (14 hom.)
• Consequence: MYH14 NM_001145809.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.72
• Publications: 14 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=0.010005832).
• BP6: Variant 19-50301724-C-T is Benign according to our data. Variant chr19-50301724-C-T is described in ClinVar as Benign. ClinVar VariationId is 504620.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00206 (314/152252) while in subpopulation NFE AF = 0.000515 (35/68016). AF 95% confidence interval is 0.000379. There are 5 homozygotes in GnomAd4. There are 231 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 314 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.5533C>T	p.Arg1845Trp	missense	Exon 40 of 43	NP_001139281.1	Q7Z406-2
	MYH14	NM_001077186.2		c.5434C>T	p.Arg1812Trp	missense	Exon 39 of 42	NP_001070654.1	Q7Z406-6
	MYH14	NM_024729.4		c.5410C>T	p.Arg1804Trp	missense	Exon 38 of 41	NP_079005.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH14	ENST00000642316.2	MANE Select	c.5533C>T	p.Arg1845Trp	missense	Exon 40 of 43	ENSP00000493594.1	Q7Z406-2
	MYH14	ENST00000425460.6	TSL:5	c.5434C>T	p.Arg1812Trp	missense	Exon 39 of 42	ENSP00000407879.1	Q7Z406-6
	MYH14	ENST00000598205.5	TSL:5	c.5434C>T	p.Arg1812Trp	missense	Exon 39 of 42	ENSP00000472543.1	Q7Z406-6

Frequencies

GnomAD3 genomes AF: 0.00206 AC: 314 AN: 152134 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0262

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000515

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00221 AC: 551 AN: 248870 AF XY: 0.00220

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0233

Gnomad NFE exome AF: 0.000320

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.000934 AC: 1365 AN: 1461600 Hom.: 14 Cov.: 31 AF XY: 0.000939 AC XY: 683 AN XY: 727086

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.0000894 AC: 4 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86254

European-Finnish (FIN) AF: 0.0198 AC: 1059 AN: 53394

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5764

European-Non Finnish (NFE) AF: 0.000246 AC: 273 AN: 1111804

Other (OTH) AF: 0.000431 AC: 26 AN: 60364

GnomAD4 genome AF: 0.00206 AC: 314 AN: 152252 Hom.: 5 Cov.: 32 AF XY: 0.00310 AC XY: 231 AN XY: 74446

African (AFR) AF: 0.00 AC: 0 AN: 41546

American (AMR) AF: 0.0000654 AC: 1 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

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

European-Finnish (FIN) AF: 0.0262 AC: 278 AN: 10604

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

European-Non Finnish (NFE) AF: 0.000515 AC: 35 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000264 Hom.: 0

Bravo AF: 0.000106

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000473 AC: 4

ExAC AF: 0.00145 AC: 175

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	MYH14-related disorder (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D
Eigen	Benign	0.14
Eigen_PC	Benign	0.082
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	1.0	D
MetaRNN	Benign	0.010	T
MetaSVM	Uncertain	-0.022	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		2.7
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Uncertain	0.58
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.017	D
Polyphen		0.84	P
Vest4		0.87
MVP		0.79
MPC		0.26
ClinPred		0.11	T
GERP RS		0.27
Varity_R		0.21
gMVP		0.58
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: rs199600574; hg19: chr19-50804981; COSMIC: COSV99221934;