rs587776357

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001145809.2(MYH14):​c.3468-3C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0225 in 1,611,082 control chromosomes in the GnomAD database, including 503 homozygotes. 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 Benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 42 hom., cov: 33)
Exomes 𝑓: 0.023 ( 461 hom. )

Consequence

MYH14
NM_001145809.2 splice_region, splice_polypyrimidine_tract, intron

Scores

2
Splicing: ADA: 0.0006063
2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8O:1

Conservation

PhyloP100: 1.76
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.62).
BP6
Variant 19-50275988-C-T is Benign according to our data. Variant chr19-50275988-C-T is described in ClinVar as [Benign]. Clinvar id is 44066.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50275988-C-T is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0171 (2604/152318) while in subpopulation NFE AF= 0.0261 (1778/68026). AF 95% confidence interval is 0.0251. There are 42 homozygotes in gnomad4. There are 1150 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High AC in GnomAd4 at 2604 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MYH14NM_001145809.2 linkuse as main transcriptc.3468-3C>T splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant ENST00000642316.2 NP_001139281.1
MYH14NM_001077186.2 linkuse as main transcriptc.3369-3C>T splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant NP_001070654.1
MYH14NM_024729.4 linkuse as main transcriptc.3345-3C>T splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant NP_079005.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MYH14ENST00000642316.2 linkuse as main transcriptc.3468-3C>T splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant NM_001145809.2 ENSP00000493594 Q7Z406-2

Frequencies

GnomAD3 genomes
AF:
0.0171
AC:
2605
AN:
152200
Hom.:
42
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00490
Gnomad AMI
AF:
0.0340
Gnomad AMR
AF:
0.0193
Gnomad ASJ
AF:
0.0415
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00828
Gnomad FIN
AF:
0.00490
Gnomad MID
AF:
0.0316
Gnomad NFE
AF:
0.0261
Gnomad OTH
AF:
0.0249
GnomAD3 exomes
AF:
0.0177
AC:
4276
AN:
242056
Hom.:
59
AF XY:
0.0181
AC XY:
2398
AN XY:
132318
show subpopulations
Gnomad AFR exome
AF:
0.00358
Gnomad AMR exome
AF:
0.0152
Gnomad ASJ exome
AF:
0.0395
Gnomad EAS exome
AF:
0.000112
Gnomad SAS exome
AF:
0.00837
Gnomad FIN exome
AF:
0.00645
Gnomad NFE exome
AF:
0.0257
Gnomad OTH exome
AF:
0.0227
GnomAD4 exome
AF:
0.0231
AC:
33626
AN:
1458764
Hom.:
461
Cov.:
31
AF XY:
0.0226
AC XY:
16368
AN XY:
725514
show subpopulations
Gnomad4 AFR exome
AF:
0.00362
Gnomad4 AMR exome
AF:
0.0162
Gnomad4 ASJ exome
AF:
0.0398
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00865
Gnomad4 FIN exome
AF:
0.00822
Gnomad4 NFE exome
AF:
0.0262
Gnomad4 OTH exome
AF:
0.0215
GnomAD4 genome
AF:
0.0171
AC:
2604
AN:
152318
Hom.:
42
Cov.:
33
AF XY:
0.0154
AC XY:
1150
AN XY:
74482
show subpopulations
Gnomad4 AFR
AF:
0.00488
Gnomad4 AMR
AF:
0.0193
Gnomad4 ASJ
AF:
0.0415
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00808
Gnomad4 FIN
AF:
0.00490
Gnomad4 NFE
AF:
0.0261
Gnomad4 OTH
AF:
0.0246
Alfa
AF:
0.0243
Hom.:
29
Bravo
AF:
0.0179
Asia WGS
AF:
0.00433
AC:
15
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:8Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:4
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, criteria provided, single submitterclinical testingGeneDxNov 21, 2017This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Feb 09, 2015- -
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineApr 30, 20123468-3C>T in Intron 27 of MYH14: This variant is not expected to have clinical s ignificance because it has been identified in 2.5% (165/6628) of European Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs78192108). -
not provided Benign:3
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsMar 13, 2019- -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Autosomal dominant nonsyndromic hearing loss 4A Benign:1Other:1
not provided, no classification providedliterature onlyGenomic Research Center, Shahid Beheshti University of Medical Sciences-- -
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.62
CADD
Benign
11
DANN
Benign
0.76

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.00061
dbscSNV1_RF
Benign
0.036
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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs78192108; hg19: chr19-50779245; API