chr11-77155908-C-T

Variant names:

• chr11-77155908-C-T
• rs781811444
• NM_000260.4:c.287C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM5 PP3 PP5

The NM_000260.4(MYO7A):​c.287C>T​(p.Thr96Met) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000113 in 1,596,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/24 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T96K) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: MYO7A NM_000260.4 missense, splice_region
• Scores: Splicing: ADA: 0.9750
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 7.55
• Publications: 4 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, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, G2P
• Usher syndrome type 1

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

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

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_000260.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-77155908-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3601466.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 11-77155908-C-T is Pathogenic according to our data. Variant chr11-77155908-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 179974.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO7A	NM_000260.4	MANE Select	c.287C>T	p.Thr96Met	missense splice_region	Exon 5 of 49	NP_000251.3
	MYO7A	NM_001127180.2		c.287C>T	p.Thr96Met	missense splice_region	Exon 5 of 49	NP_001120652.1
	MYO7A	NM_001369365.1		c.254C>T	p.Thr85Met	missense splice_region	Exon 6 of 50	NP_001356294.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO7A	ENST00000409709.9	TSL:1 MANE Select	c.287C>T	p.Thr96Met	missense splice_region	Exon 5 of 49	ENSP00000386331.3
	MYO7A	ENST00000458637.6	TSL:1	c.287C>T	p.Thr96Met	missense splice_region	Exon 5 of 49	ENSP00000392185.2
	MYO7A	ENST00000409619.6	TSL:1	c.254C>T	p.Thr85Met	missense splice_region	Exon 6 of 50	ENSP00000386635.2

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152246 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000130 AC: 3 AN: 230894 AF XY: 0.0000240

Gnomad AFR exome AF: 0.0000717

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: 0.00

GnomAD4 exome AF: 0.00000554 AC: 8 AN: 1444528 Hom.: 0 Cov.: 31 AF XY: 0.00000559 AC XY: 4 AN XY: 716076

African (AFR) AF: 0.0000302 AC: 1 AN: 33144

American (AMR) AF: 0.00 AC: 0 AN: 43166

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25596

East Asian (EAS) AF: 0.00 AC: 0 AN: 39108

South Asian (SAS) AF: 0.0000360 AC: 3 AN: 83364

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 0.00000363 AC: 4 AN: 1102024

Other (OTH) AF: 0.00 AC: 0 AN: 59788

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152246 Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6 AN XY: 74386

African (AFR) AF: 0.000193 AC: 8 AN: 41466

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68050

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00000995 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Jul 21, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 96 of the MYO7A protein (p.Thr96Met). This variant is present in population databases (rs781811444, gnomAD 0.01%). This missense change has been observed in individual(s) with non-syndromic deafness (PMID: 27344577). ClinVar contains an entry for this variant (Variation ID: 179974). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Rare genetic deafness Pathogenic:1

Nov 05, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Thr96Met variant in MYO7A has been identified by our laboratory in one ind ividual with sensorineural hearing loss and retinitis pigmentosa and segregated with disease in one affected relative. Both individuals carried this variant in trans with a second pathogenic variant in MYO7A. Computational prediction tools and conservation analyses suggest that the p.Thr98Met variant may impact the pro tein, though this information is not predictive enough to determine pathogenicit y. However, the presence of this variant in combination with a reported pathogen ic variant and in an individual with hearing loss and retinitis pigmentosa, incr eases the likelihood that the p.Thr96Met variant is pathogenic. In summary, alth ough additional studies are required to fully establish its clinical significanc e, this variant is likely pathogenic.

not specified Uncertain:1

Apr 23, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MYO7A c.287C>T (p.Thr96Met) results in a non-conservative amino acid change located in the Myosin head, motor domain (IPR001609) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.3e-05 in 230894 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.287C>T has been reported in the literature in individuals affected with hearing loss (Yan_2016). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 27344577). ClinVar contains an entry for this variant (Variation ID: 179974). Based on the evidence outlined above, the variant was classified as uncertain significance.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		7.6
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.99
MutPred		0.95		Gain of MoRF binding (P = 0.2767)
MVP		0.95
MPC		0.35
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.64
gMVP		0.88
Mutation Taster		=37/63	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Pathogenic	0.73
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: rs781811444; hg19: chr11-76866954; COSMIC: COSV68685635;