NM_001145809.2:c.4753-5A>G

Variant names:

• chr19-50289431-A-G
• rs118097099
• NM_001145809.2:c.4753-5A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001145809.2(MYH14):​c.4753-5A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000348 in 1,603,270 control chromosomes in the GnomAD database, including 2 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00055 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (0 hom.)
• Consequence: MYH14 NM_001145809.2 splice_region, intron
• Scores: Splicing: ADA: 0.0001489
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.331
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 19-50289431-A-G is Benign according to our data. Variant chr19-50289431-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 226745.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000552 (84/152194) while in subpopulation EAS AF = 0.0149 (77/5180). AF 95% confidence interval is 0.0122. There are 2 homozygotes in GnomAd4. There are 48 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 84 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.4753-5A>G		splice_region intron	N/A	NP_001139281.1	Q7Z406-2
	MYH14	NM_001077186.2		c.4654-5A>G		splice_region intron	N/A	NP_001070654.1	Q7Z406-6
	MYH14	NM_024729.4		c.4630-5A>G		splice_region intron	N/A	NP_079005.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH14	ENST00000642316.2	MANE Select	c.4753-5A>G		splice_region intron	N/A	ENSP00000493594.1	Q7Z406-2
	MYH14	ENST00000425460.6	TSL:5	c.4654-5A>G		splice_region intron	N/A	ENSP00000407879.1	Q7Z406-6
	MYH14	ENST00000598205.5	TSL:5	c.4654-5A>G		splice_region intron	N/A	ENSP00000472543.1	Q7Z406-6

Frequencies

GnomAD3 genomes AF: 0.000552 AC: 84 AN: 152076 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0148

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.00112 AC: 259 AN: 232236 AF XY: 0.00101

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000207

Gnomad EAS exome AF: 0.0147

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000191

Gnomad OTH exome AF: 0.000348

GnomAD4 exome AF: 0.000327 AC: 474 AN: 1451076 Hom.: 0 Cov.: 32 AF XY: 0.000308 AC XY: 222 AN XY: 720642

African (AFR) AF: 0.00 AC: 0 AN: 33234

American (AMR) AF: 0.00 AC: 0 AN: 43216

Ashkenazi Jewish (ASJ) AF: 0.000193 AC: 5 AN: 25902

East Asian (EAS) AF: 0.0109 AC: 426 AN: 39220

South Asian (SAS) AF: 0.000131 AC: 11 AN: 84010

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52170

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00000542 AC: 6 AN: 1107514

Other (OTH) AF: 0.000433 AC: 26 AN: 60056

GnomAD4 genome AF: 0.000552 AC: 84 AN: 152194 Hom.: 2 Cov.: 32 AF XY: 0.000645 AC XY: 48 AN XY: 74438

African (AFR) AF: 0.00 AC: 0 AN: 41514

American (AMR) AF: 0.000131 AC: 2 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.0149 AC: 77 AN: 5180

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67980

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

Alfa AF: 0.0000958 Hom.: 0

Bravo AF: 0.000695

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Autosomal dominant nonsyndromic hearing loss 4A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	6.5
DANN	Benign	0.80
PhyloP100		-0.33
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00015
dbscSNV1_RF	Benign	0.0040
SpliceAI score (max)		0.070		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: rs118097099; hg19: chr19-50792688;