19-50252726-C-T

Variant names:

• chr19-50252726-C-T
• rs376267080
• NM_001145809.2:c.1918C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001145809.2(MYH14):​c.1918C>T​(p.Arg640Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000203 in 1,595,570 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts 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. R640G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (2 hom.)
• Consequence: MYH14 NM_001145809.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 1.99
• Publications: 1 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: 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.030691683).
• BP6: Variant 19-50252726-C-T is Benign according to our data. Variant chr19-50252726-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 178416.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000236 (36/152280) while in subpopulation SAS AF = 0.00124 (6/4820). AF 95% confidence interval is 0.000813. There are 0 homozygotes in GnomAd4. There are 21 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 36 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH14	NM_001145809.2	MANE Select	c.1918C>T	p.Arg640Trp	missense	Exon 16 of 43	NP_001139281.1
	MYH14	NM_001077186.2		c.1918C>T	p.Arg640Trp	missense	Exon 16 of 42	NP_001070654.1
	MYH14	NM_024729.4		c.1894C>T	p.Arg632Trp	missense	Exon 15 of 41	NP_079005.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH14	ENST00000642316.2	MANE Select	c.1918C>T	p.Arg640Trp	missense	Exon 16 of 43	ENSP00000493594.1
	MYH14	ENST00000599920.5	TSL:1	c.1918C>T	p.Arg640Trp	missense	Exon 16 of 24	ENSP00000469573.1
	MYH14	ENST00000425460.6	TSL:5	c.1918C>T	p.Arg640Trp	missense	Exon 16 of 42	ENSP00000407879.1

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152162 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000449 AC: 98 AN: 218474 AF XY: 0.000568

Gnomad AFR exome AF: 0.000159

Gnomad AMR exome AF: 0.000322

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000819

Gnomad OTH exome AF: 0.000362

GnomAD4 exome AF: 0.000200 AC: 288 AN: 1443290 Hom.: 2 Cov.: 30 AF XY: 0.000242 AC XY: 173 AN XY: 716216

African (AFR) AF: 0.000303 AC: 10 AN: 32976

American (AMR) AF: 0.000310 AC: 13 AN: 41952

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25774

East Asian (EAS) AF: 0.0000259 AC: 1 AN: 38646

South Asian (SAS) AF: 0.00197 AC: 164 AN: 83060

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51888

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.0000770 AC: 85 AN: 1103494

Other (OTH) AF: 0.000251 AC: 15 AN: 59744

GnomAD4 genome AF: 0.000236 AC: 36 AN: 152280 Hom.: 0 Cov.: 32 AF XY: 0.000282 AC XY: 21 AN XY: 74454

African (AFR) AF: 0.000120 AC: 5 AN: 41548

American (AMR) AF: 0.00124 AC: 19 AN: 15288

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

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

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68036

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

Alfa AF: 0.000110 Hom.: 0

Bravo AF: 0.000170

ESP6500AA AF: 0.000231 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000421 AC: 51

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	MYH14-related disorder (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.083
FATHMM_MKL	Benign	0.69	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.031	T
MetaSVM	Uncertain	0.25	D
MutationAssessor	Benign	1.3	L
PhyloP100		2.0
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-4.0	D
REVEL	Uncertain	0.46
Sift	Benign	0.044	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.070	B
Vest4		0.50
MVP		0.77
MPC		0.48
ClinPred		0.048	T
GERP RS		2.0
Varity_R		0.17
gMVP		0.59
Mutation Taster		=90/10	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: rs376267080; hg19: chr19-50755983; COSMIC: COSV51816114; COSMIC: COSV51816114;