rs590722

Variant names:

• chr19-50210456-C-A
• rs590722
• NM_001145809.2:c.91C>A

Your query was ambiguous. Multiple possible variants found:

• chr19-50210456-C-A
• chr19-50210456-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001145809.2(MYH14):​c.91C>A​(p.Pro31Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.15 in 1,547,002 control chromosomes in the GnomAD database, including 17,969 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict 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. P31R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.15 (1856 hom., cov: 32)
  • Exomes 𝑓: 0.15 (16113 hom.)
• Consequence: MYH14 NM_001145809.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.179
• Publications: 15 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=0.00569883).
• BP6: Variant 19-50210456-C-A is Benign according to our data. Variant chr19-50210456-C-A is described in ClinVar as Benign. ClinVar VariationId is 44081.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.228 is higher than 0.05.

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.91C>A	p.Pro31Thr	missense	Exon 2 of 43	NP_001139281.1	Q7Z406-2
	MYH14	NM_001077186.2		c.91C>A	p.Pro31Thr	missense	Exon 2 of 42	NP_001070654.1	Q7Z406-6
	MYH14	NM_024729.4		c.91C>A	p.Pro31Thr	missense	Exon 2 of 41	NP_079005.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH14	ENST00000642316.2	MANE Select	c.91C>A	p.Pro31Thr	missense	Exon 2 of 43	ENSP00000493594.1	Q7Z406-2
	MYH14	ENST00000599920.5	TSL:1	c.91C>A	p.Pro31Thr	missense	Exon 2 of 24	ENSP00000469573.1	M0QY43
	MYH14	ENST00000425460.6	TSL:5	c.91C>A	p.Pro31Thr	missense	Exon 2 of 42	ENSP00000407879.1	Q7Z406-6

Frequencies

GnomAD3 genomes AF: 0.152 AC: 23147 AN: 152060 Hom.: 1854 Cov.: 32

Gnomad AFR AF: 0.157

Gnomad AMI AF: 0.126

Gnomad AMR AF: 0.160

Gnomad ASJ AF: 0.135

Gnomad EAS AF: 0.238

Gnomad SAS AF: 0.201

Gnomad FIN AF: 0.119

Gnomad MID AF: 0.176

Gnomad NFE AF: 0.144

Gnomad OTH AF: 0.146

GnomAD2 exomes AF: 0.167 AC: 24215 AN: 145258 AF XY: 0.170

Gnomad AFR exome AF: 0.182

Gnomad AMR exome AF: 0.150

Gnomad ASJ exome AF: 0.143

Gnomad EAS exome AF: 0.285

Gnomad FIN exome AF: 0.127

Gnomad NFE exome AF: 0.153

Gnomad OTH exome AF: 0.150

GnomAD4 exome AF: 0.150 AC: 209298 AN: 1394830 Hom.: 16113 Cov.: 33 AF XY: 0.152 AC XY: 104408 AN XY: 688820

African (AFR) AF: 0.160 AC: 4872 AN: 30432

American (AMR) AF: 0.150 AC: 5350 AN: 35774

Ashkenazi Jewish (ASJ) AF: 0.144 AC: 3562 AN: 24740

East Asian (EAS) AF: 0.221 AC: 7798 AN: 35362

South Asian (SAS) AF: 0.191 AC: 15128 AN: 79274

European-Finnish (FIN) AF: 0.127 AC: 5989 AN: 47260

Middle Eastern (MID) AF: 0.144 AC: 811 AN: 5632

European-Non Finnish (NFE) AF: 0.145 AC: 156831 AN: 1078738

Other (OTH) AF: 0.155 AC: 8957 AN: 57618

GnomAD4 genome AF: 0.152 AC: 23171 AN: 152172 Hom.: 1856 Cov.: 32 AF XY: 0.152 AC XY: 11347 AN XY: 74418

African (AFR) AF: 0.157 AC: 6530 AN: 41524

American (AMR) AF: 0.160 AC: 2454 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.135 AC: 468 AN: 3468

East Asian (EAS) AF: 0.239 AC: 1235 AN: 5174

South Asian (SAS) AF: 0.200 AC: 967 AN: 4826

European-Finnish (FIN) AF: 0.119 AC: 1261 AN: 10594

Middle Eastern (MID) AF: 0.179 AC: 52 AN: 290

European-Non Finnish (NFE) AF: 0.144 AC: 9778 AN: 67978

Other (OTH) AF: 0.147 AC: 311 AN: 2112

Alfa AF: 0.149 Hom.: 694

Bravo AF: 0.155

TwinsUK AF: 0.146 AC: 541

ALSPAC AF: 0.150 AC: 580

ESP6500AA AF: 0.108 AC: 319

ESP6500EA AF: 0.116 AC: 784

ExAC AF: 0.119 AC: 12355

Asia WGS AF: 0.217 AC: 751 AN: 3470

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Autosomal dominant nonsyndromic hearing loss 4A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Benign	0.095	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.067	N
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0057	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L
PhyloP100		-0.18
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.094
Sift	Uncertain	0.022	D
Sift4G	Benign	0.12	T
Polyphen		0.063	B
Vest4		0.072
MPC		0.81
ClinPred		0.0045	T
GERP RS		2.2
PromoterAI		-0.038	Neutral
Varity_R		0.079
gMVP		0.31
Mutation Taster		=100/0	polymorphism (auto)

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: rs590722; hg19: chr19-50713713; COSMIC: COSV51809664;