rs886054586

Variant names:

• chr19-50210357-C-A
• rs886054586
• NM_001145809.2:c.-3-6C>A

Your query was ambiguous. Multiple possible variants found:

• chr19-50210357-C-A
• chr19-50210357-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001145809.2(MYH14):​c.-3-6C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000698 in 1,432,632 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: MYH14 NM_001145809.2 splice_region, intron
• Scores: Splicing: ADA: 0.005622
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.720
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH14	NM_001145809.2	c.-3-6C>A		splice_region_variant, intron_variant	Intron 1 of 42	ENST00000642316.2	NP_001139281.1
MYH14	NM_001077186.2	c.-3-6C>A		splice_region_variant, intron_variant	Intron 1 of 41		NP_001070654.1
MYH14	NM_024729.4	c.-3-6C>A		splice_region_variant, 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.-3-6C>A		splice_region_variant, intron_variant	Intron 1 of 42		NM_001145809.2	ENSP00000493594.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.98e-7 AC: 1 AN: 1432632 Hom.: 0 Cov.: 31 AF XY: 0.00000141 AC XY: 1 AN XY: 711426

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30890

American (AMR) AF: 0.00 AC: 0 AN: 42080

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25282

East Asian (EAS) AF: 0.00 AC: 0 AN: 37416

South Asian (SAS) AF: 0.00 AC: 0 AN: 82608

European-Finnish (FIN) AF: 0.0000198 AC: 1 AN: 50482

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5694

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1099184

Other (OTH) AF: 0.00 AC: 0 AN: 58996

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	9.2
DANN	Benign	0.84
PhyloP100		0.72
PromoterAI		0.0023	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0056
dbscSNV1_RF	Benign	0.070
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: rs886054586; hg19: chr19-50713614;