rs587776357

Variant names:

• chr19-50275988-C-T
• rs78192108
• NM_001145809.2:c.3468-3C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-50275988-C-T
• chr19-50275988-C-A

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.3468-3C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0225 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, intron
• Scores: Splicing: ADA: 0.0006063
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: 1.76
• 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=-0.62).
• BP6: Variant 19-50275988-C-T is Benign according to our data. Variant chr19-50275988-C-T is described in ClinVar as Benign. ClinVar VariationId is 44066.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2604 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.3468-3C>T		splice_region intron	N/A	NP_001139281.1	Q7Z406-2
	MYH14	NM_001077186.2		c.3369-3C>T		splice_region intron	N/A	NP_001070654.1	Q7Z406-6
	MYH14	NM_024729.4		c.3345-3C>T		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.3468-3C>T		splice_region intron	N/A	ENSP00000493594.1	Q7Z406-2
	MYH14	ENST00000425460.6	TSL:5	c.3369-3C>T		splice_region intron	N/A	ENSP00000407879.1	Q7Z406-6
	MYH14	ENST00000598205.5	TSL:5	c.3369-3C>T		splice_region intron	N/A	ENSP00000472543.1	Q7Z406-6

Frequencies

GnomAD3 genomes AF: 0.0171 AC: 2605 AN: 152200 Hom.: 42 Cov.: 33

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

GnomAD2 exomes AF: 0.0177 AC: 4276 AN: 242056 AF XY: 0.0181

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 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

African (AFR) AF: 0.00362 AC: 121 AN: 33450

American (AMR) AF: 0.0162 AC: 723 AN: 44594

Ashkenazi Jewish (ASJ) AF: 0.0398 AC: 1037 AN: 26058

East Asian (EAS) AF: 0.00 AC: 0 AN: 39624

South Asian (SAS) AF: 0.00865 AC: 743 AN: 85852

European-Finnish (FIN) AF: 0.00822 AC: 434 AN: 52776

Middle Eastern (MID) AF: 0.0215 AC: 124 AN: 5760

European-Non Finnish (NFE) AF: 0.0262 AC: 29146 AN: 1110408

Other (OTH) AF: 0.0215 AC: 1298 AN: 60242

GnomAD4 genome AF: 0.0171 AC: 2604 AN: 152318 Hom.: 42 Cov.: 33 AF XY: 0.0154 AC XY: 1150 AN XY: 74482

African (AFR) AF: 0.00488 AC: 203 AN: 41572

American (AMR) AF: 0.0193 AC: 295 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0415 AC: 144 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00808 AC: 39 AN: 4828

European-Finnish (FIN) AF: 0.00490 AC: 52 AN: 10618

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0261 AC: 1778 AN: 68026

Other (OTH) AF: 0.0246 AC: 52 AN: 2114

Alfa AF: 0.0243 Hom.: 29

Bravo AF: 0.0179

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	11
DANN	Benign	0.76
PhyloP100		1.8
Mutation Taster		=89/11	polymorphism (auto)

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

Other links and lift over

dbSNP: rs78192108; hg19: chr19-50779245;