chr11-77160220-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_000260.4(MYO7A):c.1138G>A(p.Glu380Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000699 in 1,429,776 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E380E) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000070 ( 0 hom. )

Consequence

MYO7A
NM_000260.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 9.99

Variant links:

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 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.918

PP5

Variant 11-77160220-G-A is Pathogenic according to our data. Variant chr11-77160220-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 228998.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO7A	NM_000260.4 link	c.1138G>A	p.Glu380Lys	missense_variant	Exon 11 of 49	ENST00000409709.9	NP_000251.3	Q13402-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MYO7A	ENST00000409709.9 link	c.1138G>A	p.Glu380Lys	missense_variant	Exon 11 of 49	1	NM_000260.4	ENSP00000386331.3	Q13402-1
MYO7A	ENST00000458637.6 link	c.1138G>A	p.Glu380Lys	missense_variant	Exon 11 of 49	1		ENSP00000392185.2	Q13402-2
MYO7A	ENST00000409619.6 link	c.1105G>A	p.Glu369Lys	missense_variant	Exon 12 of 50	1		ENSP00000386635.2	Q13402-8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000510

AC:

AN:

196074

AF XY:

0.00000947

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000118

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000699

AC:

AN:

1429776

Hom.:

Cov.:

AF XY:

0.00000706

AC XY:

AN XY:

708064

show subpopulations

Gnomad4 AFR exome

AF:

0.00

AC:

AN:

32682

Gnomad4 AMR exome

AF:

0.00

AC:

AN:

40514

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

25568

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

37630

Gnomad4 SAS exome

AF:

0.00

AC:

AN:

81120

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

50678

Gnomad4 NFE exome

AF:

0.00000912

AC:

AN:

1096698

Gnomad4 Remaining exome

AF:

0.00

AC:

AN:

59208

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Usher syndrome type 1

Pathogenic:1

Feb 10, 2025

Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

May 05, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Glu380Lys variant in MYO7A has been reported in one Caucasian individual w ith Usher syndrome who carried a second variant of uncertain significance in MYO 7A (Le Quesne Stabej 2012). Data from large population studies are insufficient to assess the frequency of this variant. Computational prediction tools and cons ervation analyses suggest that the p.Glu380Lys variant may impact the protein, t hough this information is not predictive enough to determine pathogenicity. In s ummary, the clinical significance of the p.Glu380Lys variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.95

D;D;.;.

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D;D;D

M_CAP

Pathogenic

0.40

MetaRNN

Pathogenic

0.92

D;D;D;D

MetaSVM

Uncertain

0.22

MutationAssessor

Pathogenic

3.2

M;.;M;.

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-3.7

D;.;D;D

REVEL

Pathogenic

0.85

Sift

Uncertain

0.0020

D;.;D;D

Sift4G

Uncertain

0.020

D;D;D;D

Polyphen

0.049

B;.;.;.

Vest4

0.96

MutPred

0.74

Gain of methylation at E380 (P = 0.0162);Gain of methylation at E380 (P = 0.0162);Gain of methylation at E380 (P = 0.0162);.;

MVP

0.90

MPC

0.099

ClinPred

0.96

GERP RS

5.1

Varity_R

0.90

gMVP

0.85

Mutation Taster

=11/89

disease causing

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over