NM_000260.4:c.1258A>T

Variant names:

• chr11-77161030-A-T
• rs782539587
• NM_000260.4:c.1258A>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000260.4(MYO7A):​c.1258A>T​(p.Lys420*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000958 in 1,461,390 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: MYO7A NM_000260.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 5.04
• Publications: 9 publications found

Genes affected

MYO7A (HGNC:7606): (myosin VIIA) This gene is a member of the myosin gene family. Myosins are mechanochemical proteins characterized by the presence of a motor domain, an actin-binding domain, a neck domain that interacts with other proteins, and a tail domain that serves as an anchor. This gene encodes an unconventional myosin with a very short tail. Defects in this gene are associated with the mouse shaker-1 phenotype and the human Usher syndrome 1B which are characterized by deafness, reduced vestibular function, and (in human) retinal degeneration. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2008]

MYO7A Gene-Disease associations (from GenCC):

• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive nonsyndromic hearing loss 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• Usher syndrome type 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Usher syndrome type 1B

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• autosomal dominant nonsyndromic hearing loss 11

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Usher syndrome type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 11-77161030-A-T is Pathogenic according to our data. Variant chr11-77161030-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 504508.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000260.4. 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
	MYO7A	NM_000260.4	MANE Select	c.1258A>T	p.Lys420*	stop_gained	Exon 12 of 49	NP_000251.3	Q13402-1
	MYO7A	NM_001127180.2		c.1258A>T	p.Lys420*	stop_gained	Exon 12 of 49	NP_001120652.1	Q13402-2
	MYO7A	NM_001369365.1		c.1225A>T	p.Lys409*	stop_gained	Exon 13 of 50	NP_001356294.1	Q13402-8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO7A	ENST00000409709.9	TSL:1 MANE Select	c.1258A>T	p.Lys420*	stop_gained	Exon 12 of 49	ENSP00000386331.3	Q13402-1
	MYO7A	ENST00000458637.6	TSL:1	c.1258A>T	p.Lys420*	stop_gained	Exon 12 of 49	ENSP00000392185.2	Q13402-2
	MYO7A	ENST00000409619.6	TSL:1	c.1225A>T	p.Lys409*	stop_gained	Exon 13 of 50	ENSP00000386635.2	Q13402-8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000161 AC: 4 AN: 248542 AF XY: 0.0000222

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000996

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000887

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461390 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10 AN XY: 726918

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000929 AC: 8 AN: 86128

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111752

Other (OTH) AF: 0.0000166 AC: 1 AN: 60368

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000331 AC: 4

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	not provided (3)
2	-	-	Usher syndrome type 1;C1832475:Autosomal dominant nonsyndromic hearing loss 11;C1838701:Autosomal recessive nonsyndromic hearing loss 2 (2)
1	-	-	Autosomal recessive nonsyndromic hearing loss 2 (1)
1	-	-	Hearing loss, autosomal recessive (1)
1	-	-	Monogenic hearing loss (1)
1	-	-	Rare genetic deafness (1)
1	-	-	Usher syndrome type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Pathogenic	0.76
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		5.0
Vest4		0.94
GERP RS		4.2
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs782539587; hg19: chr11-76872076;