rs757255560

Variant names:

• chr19-50309626-T-C
• rs757255560
• NM_001145809.2:c.5961-14T>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001145809.2(MYH14):​c.5961-14T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000162 in 1,542,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0000070 (0 hom., cov: 26)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: MYH14 NM_001145809.2 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.198
• 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: 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 19-50309626-T-C is Benign according to our data. Variant chr19-50309626-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 227581.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome4 at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH14	NM_001145809.2	c.5961-14T>C		intron_variant	Intron 42 of 42	ENST00000642316.2	NP_001139281.1
MYH14	NM_001077186.2	c.5862-14T>C		intron_variant	Intron 41 of 41		NP_001070654.1
MYH14	NM_024729.4	c.5838-14T>C		intron_variant	Intron 40 of 40		NP_079005.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH14	ENST00000642316.2	c.5961-14T>C		intron_variant	Intron 42 of 42		NM_001145809.2	ENSP00000493594.1

Frequencies

GnomAD3 genomes AF: 0.00000704 AC: 1 AN: 142074 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000240

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000423 AC: 1 AN: 236374 AF XY: 0.00

Gnomad AFR exome AF: 0.0000697

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000171 AC: 24 AN: 1400742 Hom.: 0 Cov.: 33 AF XY: 0.0000201 AC XY: 14 AN XY: 695756

African (AFR) AF: 0.00 AC: 0 AN: 31662

American (AMR) AF: 0.00 AC: 0 AN: 42472

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24108

East Asian (EAS) AF: 0.00 AC: 0 AN: 35548

South Asian (SAS) AF: 0.00 AC: 0 AN: 84100

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5456

European-Non Finnish (NFE) AF: 0.0000206 AC: 22 AN: 1070412

Other (OTH) AF: 0.0000353 AC: 2 AN: 56624

GnomAD4 genome AF: 0.00000704 AC: 1 AN: 142074 Hom.: 0 Cov.: 26 AF XY: 0.0000145 AC XY: 1 AN XY: 68748

African (AFR) AF: 0.00 AC: 0 AN: 37806

American (AMR) AF: 0.00 AC: 0 AN: 13846

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3392

East Asian (EAS) AF: 0.00 AC: 0 AN: 4526

South Asian (SAS) AF: 0.000240 AC: 1 AN: 4174

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9186

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 304

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66006

Other (OTH) AF: 0.00 AC: 0 AN: 1950

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Feb 25, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.5961-14T>C in intron 42 of MYH14: This variant is not expected to have clinica l significance because a T>C change at this position does not diverge from the s plice consensus sequence and is therefore unlikely to impact splicing. It has be en identified in 1/5712 African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs757255560). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.7
DANN	Benign	0.70
PhyloP100		-0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs757255560; hg19: chr19-50812883;