rs876657874

Variant names:

• chr19-50293327-T-C
• rs876657874
• NM_001145809.2:c.5345+6T>C

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_001145809.2(MYH14):​c.5345+6T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000554 in 1,444,018 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: MYH14 NM_001145809.2 splice_region, intron
• Scores: Splicing: ADA: 0.8954
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.07
• 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.00000554 (8/1444018) while in subpopulation AMR AF = 0.000167 (7/41868). AF 95% confidence interval is 0.0000782. There are 0 homozygotes in GnomAdExome4. There are 6 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. 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 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH14	NM_001145809.2	c.5345+6T>C		splice_region_variant, intron_variant	Intron 38 of 42	ENST00000642316.2	NP_001139281.1
MYH14	NM_001077186.2	c.5246+6T>C		splice_region_variant, intron_variant	Intron 37 of 41		NP_001070654.1
MYH14	NM_024729.4	c.5222+6T>C		splice_region_variant, intron_variant	Intron 36 of 40		NP_079005.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH14	ENST00000642316.2	c.5345+6T>C		splice_region_variant, intron_variant	Intron 38 of 42		NM_001145809.2	ENSP00000493594.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000138 AC: 3 AN: 217922 AF XY: 0.0000170

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000978

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: 0.00000554 AC: 8 AN: 1444018 Hom.: 0 Cov.: 31 AF XY: 0.00000837 AC XY: 6 AN XY: 716616

African (AFR) AF: 0.00 AC: 0 AN: 33186

American (AMR) AF: 0.000167 AC: 7 AN: 41868

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25744

East Asian (EAS) AF: 0.00 AC: 0 AN: 38992

South Asian (SAS) AF: 0.00 AC: 0 AN: 83352

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52250

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 9.07e-7 AC: 1 AN: 1103056

Other (OTH) AF: 0.00 AC: 0 AN: 59822

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Sep 05, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis indicates that this variant does not alter splicing; Has not been previously published as pathogenic or benign to our knowledge -

Apr 04, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (ExAC no frequency). This sequence change falls in intron 36 of the MYH14 gene. It does not directly change the encoded amino acid sequence of the MYH14 protein. It affects a nucleotide within the consensus splice site of the intron. This variant has not been reported in the literature in individuals with MYH14-related conditions. ClinVar contains an entry for this variant (Variation ID: 228879). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. -

not specified Uncertain:1

Jul 30, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5345+6T>C variant in MYH14 has not been previously reported in individuals with hearing loss. Data from large population studies are insufficient to asse ss the frequency of this variant. Computational tools do not suggest an impact t o splicing. However, this information is not predictive enough to rule out patho genicity. In summary, the clinical significance of the c.5345+6T>C variant is un certain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	22
DANN	Benign	0.86
PhyloP100		2.1
Mutation Taster		=42/58	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.90
dbscSNV1_RF	Benign	0.60
SpliceAI score (max)		0.19		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: rs876657874; hg19: chr19-50796584;