chr19-50268152-A-C

Variant names:

• chr19-50268152-A-C
• rs3745503
• NM_001145809.2:c.2827-9A>C

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.2827-9A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.122 in 1,539,722 control chromosomes in the GnomAD database, including 13,451 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2021 hom., cov: 33)
  • Exomes 𝑓: 0.12 (11430 hom.)
• Consequence: MYH14 NM_001145809.2 intron
• Scores: Splicing: ADA: 0.00003119
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -2.07
• Publications: 9 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), PanelApp Australia
• peripheral neuropathy-myopathy-hoarseness-hearing loss syndrome

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• 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=-0.89).
• BP6: Variant 19-50268152-A-C is Benign according to our data. Variant chr19-50268152-A-C is described in ClinVar as Benign. ClinVar VariationId is 44060.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.23 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.2827-9A>C		intron	N/A	NP_001139281.1
	MYH14	NM_001077186.2		c.2728-9A>C		intron	N/A	NP_001070654.1
	MYH14	NM_024729.4		c.2704-9A>C		intron	N/A	NP_079005.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH14	ENST00000642316.2	MANE Select	c.2827-9A>C		intron	N/A	ENSP00000493594.1
	MYH14	ENST00000599920.5	TSL:1	c.2728-9A>C		intron	N/A	ENSP00000469573.1
	MYH14	ENST00000425460.6	TSL:5	c.2728-9A>C		intron	N/A	ENSP00000407879.1

Frequencies

GnomAD3 genomes AF: 0.148 AC: 22521 AN: 151930 Hom.: 2017 Cov.: 33

Gnomad AFR AF: 0.234

Gnomad AMI AF: 0.0592

Gnomad AMR AF: 0.0794

Gnomad ASJ AF: 0.218

Gnomad EAS AF: 0.233

Gnomad SAS AF: 0.240

Gnomad FIN AF: 0.0794

Gnomad MID AF: 0.162

Gnomad NFE AF: 0.107

Gnomad OTH AF: 0.136

GnomAD2 exomes AF: 0.140 AC: 20664 AN: 148054 AF XY: 0.146

Gnomad AFR exome AF: 0.243

Gnomad AMR exome AF: 0.0566

Gnomad ASJ exome AF: 0.214

Gnomad EAS exome AF: 0.227

Gnomad FIN exome AF: 0.0858

Gnomad NFE exome AF: 0.107

Gnomad OTH exome AF: 0.123

GnomAD4 exome AF: 0.119 AC: 164582 AN: 1387676 Hom.: 11430 Cov.: 34 AF XY: 0.122 AC XY: 83231 AN XY: 684026

African (AFR) AF: 0.240 AC: 7569 AN: 31494

American (AMR) AF: 0.0609 AC: 2171 AN: 35660

Ashkenazi Jewish (ASJ) AF: 0.213 AC: 5346 AN: 25138

East Asian (EAS) AF: 0.260 AC: 9266 AN: 35644

South Asian (SAS) AF: 0.229 AC: 18139 AN: 79090

European-Finnish (FIN) AF: 0.0851 AC: 3581 AN: 42060

Middle Eastern (MID) AF: 0.152 AC: 663 AN: 4360

European-Non Finnish (NFE) AF: 0.102 AC: 109978 AN: 1076576

Other (OTH) AF: 0.136 AC: 7869 AN: 57654

GnomAD4 genome AF: 0.148 AC: 22546 AN: 152046 Hom.: 2021 Cov.: 33 AF XY: 0.148 AC XY: 10968 AN XY: 74328

African (AFR) AF: 0.234 AC: 9701 AN: 41456

American (AMR) AF: 0.0792 AC: 1210 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.218 AC: 758 AN: 3470

East Asian (EAS) AF: 0.232 AC: 1197 AN: 5162

South Asian (SAS) AF: 0.239 AC: 1149 AN: 4816

European-Finnish (FIN) AF: 0.0794 AC: 840 AN: 10584

Middle Eastern (MID) AF: 0.161 AC: 47 AN: 292

European-Non Finnish (NFE) AF: 0.107 AC: 7296 AN: 67974

Other (OTH) AF: 0.139 AC: 294 AN: 2110

Alfa AF: 0.115 Hom.: 1413

Bravo AF: 0.149

Asia WGS AF: 0.241 AC: 836 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Autosomal dominant nonsyndromic hearing loss 4A (2)
-	-	2	not provided (2)
-	-	1	Peripheral neuropathy-myopathy-hoarseness-hearing loss syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.24
DANN	Benign	0.56
PhyloP100		-2.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000031
dbscSNV1_RF	Benign	0.012
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: rs3745503; hg19: chr19-50771409; COSMIC: COSV51826530; COSMIC: COSV51826530;