rs201986144

Variant names:

• chr19-50309669-C-A
• rs201986144
• NM_001145809.2:c.5990C>A

Your query was ambiguous. Multiple possible variants found:

• chr19-50309669-C-A
• chr19-50309669-C-G
• chr19-50309669-C-T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BS1 BS2

The NM_001145809.2(MYH14):​c.5990C>A​(p.Thr1997Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000754 in 1,458,962 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1997M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: MYH14 NM_001145809.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.35
• Publications: 4 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14999995).
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00000754 (11/1458962) while in subpopulation MID AF = 0.00139 (8/5764). AF 95% confidence interval is 0.00069. There are 0 homozygotes in GnomAdExome4. There are 7 alleles in the male GnomAdExome4 subpopulation. Median coverage is 35. This position passed quality control check.
• BS2: High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH14	NM_001145809.2	c.5990C>A	p.Thr1997Lys	missense_variant	Exon 43 of 43	ENST00000642316.2	NP_001139281.1
MYH14	NM_001077186.2	c.5891C>A	p.Thr1964Lys	missense_variant	Exon 42 of 42		NP_001070654.1
MYH14	NM_024729.4	c.5867C>A	p.Thr1956Lys	missense_variant	Exon 41 of 41		NP_079005.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH14	ENST00000642316.2	c.5990C>A	p.Thr1997Lys	missense_variant	Exon 43 of 43		NM_001145809.2	ENSP00000493594.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD2 exomes AF: 0.00000826 AC: 2 AN: 242058 AF XY: 0.00000760

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.000339

GnomAD4 exome AF: 0.00000754 AC: 11 AN: 1458962 Hom.: 0 Cov.: 35 AF XY: 0.00000965 AC XY: 7 AN XY: 725482

African (AFR) AF: 0.00 AC: 0 AN: 33392

American (AMR) AF: 0.00 AC: 0 AN: 44434

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26058

East Asian (EAS) AF: 0.00 AC: 0 AN: 39566

South Asian (SAS) AF: 0.0000351 AC: 3 AN: 85422

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53166

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110890

Other (OTH) AF: 0.00 AC: 0 AN: 60270

GnomAD4 genome Cov.: 29

Alfa AF: 0.00000900 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Uncertain	0.043	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.13	.;.;.;T;.;.;T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.67	.;T;T;T;.;T;.
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.15	T;T;T;T;T;T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	1.4	.;.;.;L;.;.;L
PhyloP100		2.4
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-1.1	.;.;N;.;.;.;.
REVEL	Uncertain	0.31
Sift	Benign	0.67	.;.;T;.;.;.;.
Sift4G	Benign	0.78	T;T;T;T;.;T;T
Polyphen		0.59	P;.;P;B;P;P;B
Vest4		0.29
MutPred		0.21		.;.;.;Gain of methylation at T1956 (P = 0.0196);.;.;Gain of methylation at T1956 (P = 0.0196);
MVP		0.87
MPC		0.19
ClinPred		0.11	T
GERP RS		3.8
Varity_R		0.18
gMVP		0.51
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs201986144; hg19: chr19-50812926;