rs35315400

Variant names:

• chr19-50231990-C-G
• rs35315400
• NM_001145809.2:c.1034C>G

Your query was ambiguous. Multiple possible variants found:

• chr19-50231990-C-G
• chr19-50231990-C-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001145809.2(MYH14):​c.1034C>G​(p.Ser345Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000395 in 1,613,954 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 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 0.0022 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00020 (1 hom.)
• Consequence: MYH14 NM_001145809.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 3.18
• Publications: 1 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008297592).
• BP6: Variant 19-50231990-C-G is Benign according to our data. Variant chr19-50231990-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 178414.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00224 (341/152394) while in subpopulation AFR AF = 0.00798 (332/41596). AF 95% confidence interval is 0.00727. There are 2 homozygotes in GnomAd4. There are 166 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 341 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001145809.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH14	NM_001145809.2	MANE Select	c.1034C>G	p.Ser345Cys	missense	Exon 10 of 43	NP_001139281.1	Q7Z406-2
	MYH14	NM_001077186.2		c.1034C>G	p.Ser345Cys	missense	Exon 10 of 42	NP_001070654.1	Q7Z406-6
	MYH14	NM_024729.4		c.1010C>G	p.Ser337Cys	missense	Exon 9 of 41	NP_079005.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH14	ENST00000642316.2	MANE Select	c.1034C>G	p.Ser345Cys	missense	Exon 10 of 43	ENSP00000493594.1	Q7Z406-2
	MYH14	ENST00000599920.5	TSL:1	c.1034C>G	p.Ser345Cys	missense	Exon 10 of 24	ENSP00000469573.1	M0QY43
	MYH14	ENST00000425460.6	TSL:5	c.1034C>G	p.Ser345Cys	missense	Exon 10 of 42	ENSP00000407879.1	Q7Z406-6

Frequencies

GnomAD3 genomes AF: 0.00223 AC: 340 AN: 152276 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00798

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000392

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

GnomAD2 exomes AF: 0.000590 AC: 147 AN: 248998 AF XY: 0.000429

Gnomad AFR exome AF: 0.00898

Gnomad AMR exome AF: 0.000203

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: 0.000165

GnomAD4 exome AF: 0.000203 AC: 297 AN: 1461560 Hom.: 1 Cov.: 31 AF XY: 0.000168 AC XY: 122 AN XY: 727058

African (AFR) AF: 0.00747 AC: 250 AN: 33480

American (AMR) AF: 0.000224 AC: 10 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53252

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111868

Other (OTH) AF: 0.000513 AC: 31 AN: 60374

GnomAD4 genome AF: 0.00224 AC: 341 AN: 152394 Hom.: 2 Cov.: 33 AF XY: 0.00223 AC XY: 166 AN XY: 74530

African (AFR) AF: 0.00798 AC: 332 AN: 41596

American (AMR) AF: 0.000392 AC: 6 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68040

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.000145 Hom.: 0

Bravo AF: 0.00249

ESP6500AA AF: 0.00912 AC: 36

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000794 AC: 96

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Autosomal dominant nonsyndromic hearing loss 4A (1)
-	1	-	Inborn genetic diseases (1)
-	-	1	MYH14-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.0083	T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	-0.28	N
PhyloP100		3.2
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.33	N
REVEL	Uncertain	0.30
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.99	D
Vest4		0.35
MVP		0.52
MPC		0.72
ClinPred		0.041	T
GERP RS		3.0
Varity_R		0.19
gMVP		0.30
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs35315400; hg19: chr19-50735247;