chr19-50210294-G-A

Variant names:

• chr19-50210294-G-A
• rs116165622
• NM_001145809.2:c.-3-69G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001145809.2(MYH14):​c.-3-69G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0096 in 1,399,822 control chromosomes in the GnomAD database, including 134 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (42 hom., cov: 32)
  • Exomes 𝑓: 0.0085 (92 hom.)
• Consequence: MYH14 NM_001145809.2 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.83
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 19-50210294-G-A is Benign according to our data. Variant chr19-50210294-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1182737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0188 (2863/152210) while in subpopulation AFR AF = 0.0419 (1741/41540). AF 95% confidence interval is 0.0403. There are 42 homozygotes in GnomAd4. There are 1402 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2863 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH14	NM_001145809.2	c.-3-69G>A		intron_variant	Intron 1 of 42	ENST00000642316.2	NP_001139281.1
MYH14	NM_001077186.2	c.-3-69G>A		intron_variant	Intron 1 of 41		NP_001070654.1
MYH14	NM_024729.4	c.-3-69G>A		intron_variant	Intron 1 of 40		NP_079005.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH14	ENST00000642316.2	c.-3-69G>A		intron_variant	Intron 1 of 42		NM_001145809.2	ENSP00000493594.1

Frequencies

GnomAD3 genomes AF: 0.0188 AC: 2858 AN: 152094 Hom.: 42 Cov.: 32

Gnomad AFR AF: 0.0419

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0194

Gnomad ASJ AF: 0.0219

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0143

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00779

Gnomad OTH AF: 0.0244

GnomAD4 exome AF: 0.00847 AC: 10573 AN: 1247612 Hom.: 92 AF XY: 0.00812 AC XY: 4979 AN XY: 613464

African (AFR) AF: 0.0432 AC: 1072 AN: 24814

American (AMR) AF: 0.0103 AC: 242 AN: 23394

Ashkenazi Jewish (ASJ) AF: 0.0232 AC: 466 AN: 20122

East Asian (EAS) AF: 0.0000328 AC: 1 AN: 30498

South Asian (SAS) AF: 0.000601 AC: 41 AN: 68246

European-Finnish (FIN) AF: 0.0120 AC: 549 AN: 45900

Middle Eastern (MID) AF: 0.0163 AC: 84 AN: 5168

European-Non Finnish (NFE) AF: 0.00766 AC: 7495 AN: 978174

Other (OTH) AF: 0.0121 AC: 623 AN: 51296

GnomAD4 genome AF: 0.0188 AC: 2863 AN: 152210 Hom.: 42 Cov.: 32 AF XY: 0.0188 AC XY: 1402 AN XY: 74420

African (AFR) AF: 0.0419 AC: 1741 AN: 41540

American (AMR) AF: 0.0194 AC: 297 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0219 AC: 76 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4830

European-Finnish (FIN) AF: 0.0143 AC: 152 AN: 10594

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.00779 AC: 530 AN: 67998

Other (OTH) AF: 0.0241 AC: 51 AN: 2114

Alfa AF: 0.0142 Hom.: 5

Bravo AF: 0.0208

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 29, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	8.4
DANN	Benign	0.77
PhyloP100		1.8
PromoterAI		0.00040	Neutral
Mutation Taster		=100/0	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: rs116165622; hg19: chr19-50713551;