NM_001145809.2:c.5678+12C>T

Variant names:

• chr19-50301881-C-T
• rs3826772
• NM_001145809.2:c.5678+12C>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.5678+12C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.837 in 1,601,276 control chromosomes in the GnomAD database, including 562,982 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.78 (47548 hom., cov: 31)
  • Exomes 𝑓: 0.84 (515434 hom.)
• Consequence: MYH14 NM_001145809.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.368
• Publications: 19 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 19-50301881-C-T is Benign according to our data. Variant chr19-50301881-C-T is described in ClinVar as Benign. ClinVar VariationId is 226747.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.85 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH14	NM_001145809.2	MANE Select	c.5678+12C>T		intron	N/A	NP_001139281.1
	MYH14	NM_001077186.2		c.5579+12C>T		intron	N/A	NP_001070654.1
	MYH14	NM_024729.4		c.5555+12C>T		intron	N/A	NP_079005.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH14	ENST00000642316.2	MANE Select	c.5678+12C>T		intron	N/A	ENSP00000493594.1
	MYH14	ENST00000425460.6	TSL:5	c.5579+12C>T		intron	N/A	ENSP00000407879.1
	MYH14	ENST00000598205.5	TSL:5	c.5579+12C>T		intron	N/A	ENSP00000472543.1

Frequencies

GnomAD3 genomes AF: 0.784 AC: 119165 AN: 151926 Hom.: 47533 Cov.: 31

Gnomad AFR AF: 0.635

Gnomad AMI AF: 0.633

Gnomad AMR AF: 0.819

Gnomad ASJ AF: 0.886

Gnomad EAS AF: 0.809

Gnomad SAS AF: 0.776

Gnomad FIN AF: 0.830

Gnomad MID AF: 0.775

Gnomad NFE AF: 0.856

Gnomad OTH AF: 0.792

GnomAD2 exomes AF: 0.829 AC: 191380 AN: 230798 AF XY: 0.829

Gnomad AFR exome AF: 0.626

Gnomad AMR exome AF: 0.862

Gnomad ASJ exome AF: 0.889

Gnomad EAS exome AF: 0.819

Gnomad FIN exome AF: 0.839

Gnomad NFE exome AF: 0.855

Gnomad OTH exome AF: 0.843

GnomAD4 exome AF: 0.842 AC: 1220279 AN: 1449232 Hom.: 515434 Cov.: 32 AF XY: 0.840 AC XY: 605299 AN XY: 720192

African (AFR) AF: 0.625 AC: 20784 AN: 33230

American (AMR) AF: 0.857 AC: 36464 AN: 42536

Ashkenazi Jewish (ASJ) AF: 0.895 AC: 23145 AN: 25850

East Asian (EAS) AF: 0.764 AC: 30075 AN: 39340

South Asian (SAS) AF: 0.779 AC: 66080 AN: 84816

European-Finnish (FIN) AF: 0.841 AC: 44171 AN: 52522

Middle Eastern (MID) AF: 0.814 AC: 4670 AN: 5740

European-Non Finnish (NFE) AF: 0.855 AC: 945182 AN: 1105214

Other (OTH) AF: 0.829 AC: 49708 AN: 59984

GnomAD4 genome AF: 0.784 AC: 119218 AN: 152044 Hom.: 47548 Cov.: 31 AF XY: 0.783 AC XY: 58199 AN XY: 74326

African (AFR) AF: 0.634 AC: 26272 AN: 41442

American (AMR) AF: 0.819 AC: 12517 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.886 AC: 3075 AN: 3470

East Asian (EAS) AF: 0.809 AC: 4173 AN: 5160

South Asian (SAS) AF: 0.776 AC: 3736 AN: 4814

European-Finnish (FIN) AF: 0.830 AC: 8773 AN: 10576

Middle Eastern (MID) AF: 0.789 AC: 232 AN: 294

European-Non Finnish (NFE) AF: 0.856 AC: 58195 AN: 67988

Other (OTH) AF: 0.791 AC: 1669 AN: 2110

Alfa AF: 0.834 Hom.: 100049

Bravo AF: 0.779

Asia WGS AF: 0.805 AC: 2799 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.014
DANN	Benign	0.53
PhyloP100		-0.37
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: rs3826772; hg19: chr19-50805138;