rs727503225

Variant names:

• chr19-50280352-C-T
• rs727503225
• NM_001145809.2:c.4259C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-50280352-C-T
• chr19-50280352-C-A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_001145809.2(MYH14):​c.4259C>T​(p.Ala1420Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000911 in 1,546,942 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A1420A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000099 (0 hom.)
• Consequence: MYH14 NM_001145809.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 0.170
• 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: 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05962336).
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000989 (138/1394786) while in subpopulation MID AF = 0.000475 (2/4208). AF 95% confidence interval is 0.0000968. There are 0 homozygotes in GnomAdExome4. There are 77 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAdExome4 at 138 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.4259C>T	p.Ala1420Val	missense	Exon 32 of 43	NP_001139281.1	Q7Z406-2
	MYH14	NM_001077186.2		c.4160C>T	p.Ala1387Val	missense	Exon 31 of 42	NP_001070654.1	Q7Z406-6
	MYH14	NM_024729.4		c.4136C>T	p.Ala1379Val	missense	Exon 30 of 41	NP_079005.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH14	ENST00000642316.2	MANE Select	c.4259C>T	p.Ala1420Val	missense	Exon 32 of 43	ENSP00000493594.1	Q7Z406-2
	MYH14	ENST00000425460.6	TSL:5	c.4160C>T	p.Ala1387Val	missense	Exon 31 of 42	ENSP00000407879.1	Q7Z406-6
	MYH14	ENST00000598205.5	TSL:5	c.4160C>T	p.Ala1387Val	missense	Exon 31 of 42	ENSP00000472543.1	Q7Z406-6

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000593 AC: 9 AN: 151730 AF XY: 0.0000621

Gnomad AFR exome AF: 0.000128

Gnomad AMR exome AF: 0.000122

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000923

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000513

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000989 AC: 138 AN: 1394786 Hom.: 0 Cov.: 32 AF XY: 0.000112 AC XY: 77 AN XY: 687546

African (AFR) AF: 0.0000635 AC: 2 AN: 31502

American (AMR) AF: 0.000141 AC: 5 AN: 35552

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25034

East Asian (EAS) AF: 0.0000841 AC: 3 AN: 35678

South Asian (SAS) AF: 0.0000380 AC: 3 AN: 78848

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49046

Middle Eastern (MID) AF: 0.000475 AC: 2 AN: 4208

European-Non Finnish (NFE) AF: 0.000113 AC: 122 AN: 1077252

Other (OTH) AF: 0.0000173 AC: 1 AN: 57666

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152156 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74320

African (AFR) AF: 0.0000241 AC: 1 AN: 41422

American (AMR) AF: 0.00 AC: 0 AN: 15282

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

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

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: 0.0000147 AC: 1 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000283 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000332 AC: 1

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	-	Autosomal dominant nonsyndromic hearing loss 4A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	13
DANN	Uncertain	0.98
DEOGEN2	Benign	0.12	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0053	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.060	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.38	N
PhyloP100		0.17
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.14
Sift	Benign	0.21	T
Sift4G	Benign	0.28	T
Polyphen		0.024	B
Vest4		0.12
MVP		0.27
MPC		0.15
ClinPred		0.015	T
GERP RS		0.12
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.019
gMVP		0.15
Mutation Taster		=94/6	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: rs727503225; hg19: chr19-50783609;