19-50210759-G-A

Variant names:

• chr19-50210759-G-A
• rs199910006
• NM_001145809.2:c.394G>A

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.394G>A​(p.Gly132Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000881 in 1,573,820 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).

• Frequency:
  • Genomes: 𝑓 0.00066 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00090 (1 hom.)
• Consequence: MYH14 NM_001145809.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: 5.62
• Publications: 2 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=0.015086144).
• BP6: Variant 19-50210759-G-A is Benign according to our data. Variant chr19-50210759-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 178410.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000663 (101/152322) while in subpopulation NFE AF = 0.00106 (72/68036). AF 95% confidence interval is 0.000861. There are 1 homozygotes in GnomAd4. There are 36 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 101 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.394G>A	p.Gly132Ser	missense	Exon 2 of 43	NP_001139281.1
	MYH14	NM_001077186.2		c.394G>A	p.Gly132Ser	missense	Exon 2 of 42	NP_001070654.1
	MYH14	NM_024729.4		c.394G>A	p.Gly132Ser	missense	Exon 2 of 41	NP_079005.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH14	ENST00000642316.2	MANE Select	c.394G>A	p.Gly132Ser	missense	Exon 2 of 43	ENSP00000493594.1
	MYH14	ENST00000599920.5	TSL:1	c.394G>A	p.Gly132Ser	missense	Exon 2 of 24	ENSP00000469573.1
	MYH14	ENST00000425460.6	TSL:5	c.394G>A	p.Gly132Ser	missense	Exon 2 of 42	ENSP00000407879.1

Frequencies

GnomAD3 genomes AF: 0.000664 AC: 101 AN: 152204 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00106

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000671 AC: 121 AN: 180202 AF XY: 0.000707

Gnomad AFR exome AF: 0.000101

Gnomad AMR exome AF: 0.0000373

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00196

Gnomad NFE exome AF: 0.00109

Gnomad OTH exome AF: 0.000212

GnomAD4 exome AF: 0.000904 AC: 1285 AN: 1421498 Hom.: 1 Cov.: 33 AF XY: 0.000884 AC XY: 622 AN XY: 703944

African (AFR) AF: 0.0000313 AC: 1 AN: 31990

American (AMR) AF: 0.0000259 AC: 1 AN: 38584

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25388

East Asian (EAS) AF: 0.0000269 AC: 1 AN: 37192

South Asian (SAS) AF: 0.0000248 AC: 2 AN: 80650

European-Finnish (FIN) AF: 0.00172 AC: 86 AN: 50132

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5714

European-Non Finnish (NFE) AF: 0.00107 AC: 1172 AN: 1093002

Other (OTH) AF: 0.000357 AC: 21 AN: 58846

GnomAD4 genome AF: 0.000663 AC: 101 AN: 152322 Hom.: 1 Cov.: 32 AF XY: 0.000483 AC XY: 36 AN XY: 74480

African (AFR) AF: 0.000216 AC: 9 AN: 41582

American (AMR) AF: 0.000131 AC: 2 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00160 AC: 17 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00106 AC: 72 AN: 68036

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000814 Hom.: 0

Bravo AF: 0.000487

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00117 AC: 10

ExAC AF: 0.000383 AC: 46

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	5	not provided (6)
-	-	2	not specified (2)
-	-	1	Autosomal dominant nonsyndromic hearing loss 4A (1)
-	-	1	MYH14-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	0.67	N
PhyloP100		5.6
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-4.3	D
REVEL	Benign	0.28
Sift	Benign	0.25	T
Sift4G	Benign	0.47	T
Polyphen		0.96	D
Vest4		0.25
MVP		0.59
MPC		0.89
ClinPred		0.049	T
GERP RS		3.3
PromoterAI		-0.063	Neutral
Varity_R		0.11
gMVP		0.53
Mutation Taster		=50/50

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: rs199910006; hg19: chr19-50714016; COSMIC: COSV99222127;