rs727505272

Variant names:

• chr19-50281696-C-T
• rs727505272
• NM_001145809.2:c.4393C>T
• MYH14 p.Arg1465Cys

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_001145809.2(MYH14):​c.4393C>T​(p.Arg1465Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000117 in 1,611,912 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R1465L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: MYH14 NM_001145809.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 2.45
• Publications: 0 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: Ambry Genetics, Orphanet, 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 -9 ACMG points.

• BP6: Variant 19-50281696-C-T is Benign according to our data. Variant chr19-50281696-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 179996.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000123 (180/1459674) while in subpopulation NFE AF = 0.00016 (178/1111494). AF 95% confidence interval is 0.000141. There are 0 homozygotes in GnomAdExome4. There are 75 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 9 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.4393C>T	p.Arg1465Cys	missense	Exon 33 of 43	NP_001139281.1	Q7Z406-2
	MYH14	NM_001077186.2		c.4294C>T	p.Arg1432Cys	missense	Exon 32 of 42	NP_001070654.1	Q7Z406-6
	MYH14	NM_024729.4		c.4270C>T	p.Arg1424Cys	missense	Exon 31 of 41	NP_079005.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH14	ENST00000642316.2	MANE Select	c.4393C>T	p.Arg1465Cys	missense	Exon 33 of 43	ENSP00000493594.1	Q7Z406-2
	MYH14	ENST00000425460.6	TSL:5	c.4294C>T	p.Arg1432Cys	missense	Exon 32 of 42	ENSP00000407879.1	Q7Z406-6
	MYH14	ENST00000598205.5	TSL:5	c.4294C>T	p.Arg1432Cys	missense	Exon 32 of 42	ENSP00000472543.1	Q7Z406-6

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152238 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.000103

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000666 AC: 16 AN: 240414 AF XY: 0.0000379

Gnomad AFR exome AF: 0.0000706

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000140

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000123 AC: 180 AN: 1459674 Hom.: 0 Cov.: 32 AF XY: 0.000103 AC XY: 75 AN XY: 726164

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44632

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26080

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86172

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52146

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5682

European-Non Finnish (NFE) AF: 0.000160 AC: 178 AN: 1111494

Other (OTH) AF: 0.0000166 AC: 1 AN: 60324

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152238 Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5 AN XY: 74378

African (AFR) AF: 0.0000241 AC: 1 AN: 41458

American (AMR) AF: 0.0000654 AC: 1 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000141 Hom.: 0

Bravo AF: 0.000113

EpiCase AF: 0.0000545

EpiControl AF: 0.0000594

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	1	not specified (2)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Uncertain	-0.083	T
MutationAssessor	Benign	1.9	L
PhyloP100		2.5
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-4.9	D
REVEL	Uncertain	0.50
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.0060	D
Varity_R		0.16
gMVP		0.40
Mutation Taster		=75/25	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs727505272;

hg19: chr19-50784953;