rs145522874

chr19-50286647-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001145809.2(MYH14):c.4705G>T(p.Ala1569Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000761 in 1,589,196 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000045 (0 hom.)
• Consequence: MYH14 NM_001145809.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 2.58

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.030436993).
• BP6: Variant 19-50286647-G-T is Benign according to our data. Variant chr19-50286647-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 164199.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000374 (57/152374) while in subpopulation AMR AF= 0.00111 (17/15304). AF 95% confidence interval is 0.000707. There are 0 homozygotes in gnomad4. There are 25 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 57 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH14	NM_001145809.2	c.4705G>T	p.Ala1569Ser	missense_variant	34/43	ENST00000642316.2
MYH14	NM_001077186.2	c.4606G>T	p.Ala1536Ser	missense_variant	33/42
MYH14	NM_024729.4	c.4582G>T	p.Ala1528Ser	missense_variant	32/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH14	ENST00000642316.2	c.4705G>T	p.Ala1569Ser	missense_variant	34/43		NM_001145809.2

Frequencies

GnomAD3 genomes AF: 0.000374 AC: 57 AN: 152256 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000892

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.0000934 AC: 19 AN: 203334 Hom.: 0 AF XY: 0.0000182 AC XY: 2 AN XY: 109888

Gnomad AFR exome AF: 0.00103

Gnomad AMR exome AF: 0.000208

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000191

GnomAD4 exome AF: 0.0000445 AC: 64 AN: 1436822 Hom.: 0 Cov.: 31 AF XY: 0.0000309 AC XY: 22 AN XY: 712250

Gnomad4 AFR exome AF: 0.00127

Gnomad4 AMR exome AF: 0.000325

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000151

GnomAD4 genome AF: 0.000374 AC: 57 AN: 152374 Hom.: 0 Cov.: 33 AF XY: 0.000336 AC XY: 25 AN XY: 74514

Gnomad4 AFR AF: 0.000890

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000253 Hom.: 0

Bravo AF: 0.000646

ESP6500AA AF: 0.000714 AC: 3

ESP6500EA AF: 0.000119 AC: 1

ExAC AF: 0.0000913 AC: 11

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 04, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 11, 2014

Variant classified as Uncertain Significance - Favor Benign. The Ala1569Ser vari ant in MYH14 has not been previously reported in individuals with hearing loss, but has been identified in 0.07% (3/4202) of African American chromosomes and 0. 01% (1/8436) European American chromosomes by the NHLBI Exome Sequencing Project , and in 1.0% (2/190) of Luhya (Kenyan) chromosomes and 0.8% (1/119) of Columbia n chromosomes by the 1000 Genomes Project (http://evs.gs.washington.edu/EVS/; db SNP rs145522874). Computational prediction tools and conservation analyses do no t provide strong support for or against an impact to the protein. In summary, wh ile the clinical significance of the Ala1569Ser variant is uncertain, its presen ce in several racially diverse populations at a range of frequencies (0.01% - 1. 0%) suggests a more likely benign role. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 03, 2024

The c.4582G>T (p.A1528S) alteration is located in exon 32 (coding exon 31) of the MYH14 gene. This alteration results from a G to T substitution at nucleotide position 4582, causing the alanine (A) at amino acid position 1528 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.34
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.030	T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.0013	T
MutationTaster	Benign	0.75	D;D;D;D
PrimateAI	Uncertain	0.68	T
Sift4G	Benign	0.71	T;T;T;T;.;T;T
Polyphen		0.88	P;.;P;P;P;P;P
Vest4		0.38
MVP		0.68
MPC		0.44
ClinPred		0.049	T
GERP RS		4.5
Varity_R		0.081
gMVP		0.095

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

Publications

LitVar

Other links and lift over

dbSNP: rs145522874; hg19: chr19-50789904;