Genetic Variant MYO7A:c.133-14C>T (chr11-77147784-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000260.4(MYO7A):c.133-14C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00125 in 1,608,070 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene MYO7A is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.0066 ( 12 hom., cov: 32)

Exomes 𝑓: 0.00069 ( 21 hom. )

Consequence

MYO7A
NM_000260.4 intron

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 2.76

Publications

0 publications found

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 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

MYO7A links:

Genome browser will be placed here

ACMG classification

Specifications for MYO7A are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.74).

BP6

Variant 11-77147784-C-T is Benign according to our data. Variant chr11-77147784-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 178476.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0066 (1006/152310) while in subpopulation AFR AF = 0.0227 (942/41582). AF 95% confidence interval is 0.0215. There are 12 homozygotes in GnomAd4. There are 453 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 12 AR,AD gene

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MYO7A	NM_000260.4	MANE Select	c.133-14C>T	intron	N/A	NP_000251.3	Q13402-1
MYO7A	NM_001127180.2		c.133-14C>T	intron	N/A	NP_001120652.1	Q13402-2
MYO7A	NM_001369365.1		c.100-14C>T	intron	N/A	NP_001356294.1	Q13402-8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MYO7A	ENST00000409709.9	TSL:1 MANE Select	c.133-14C>T	intron	N/A	ENSP00000386331.3	Q13402-1
MYO7A	ENST00000458637.6	TSL:1	c.133-14C>T	intron	N/A	ENSP00000392185.2	Q13402-2
MYO7A	ENST00000409619.6	TSL:1	c.100-14C>T	intron	N/A	ENSP00000386635.2	Q13402-8

Frequencies

GnomAD3 genomes

AF:

0.00663

AC:

1009

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0228

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00314

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00431

GnomAD2 exomes

AF:

0.00165

AC:

394

AN:

238386

AF XY:

0.00129

show subpopulations

Gnomad AFR exome

AF:

0.0260

Gnomad AMR exome

AF:

0.000681

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000568

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000925

Gnomad OTH exome

AF:

0.00171

GnomAD4 exome

AF:

0.000688

AC:

1002

AN:

1455760

Hom.:

Cov.:

AF XY:

0.000637

AC XY:

461

AN XY:

723434

show subpopulations

African (AFR)

AF:

0.0257

AC:

857

AN:

33376

American (AMR)

AF:

0.00102

AC:

AN:

44172

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25866

East Asian (EAS)

AF:

0.00

AC:

AN:

39438

South Asian (SAS)

AF:

0.0000591

AC:

AN:

84626

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52104

Middle Eastern (MID)

AF:

0.00122

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1110210

Other (OTH)

AF:

0.00140

AC:

AN:

60210

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

102

154

205

256

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

140

<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

AF:

0.00660

AC:

1006

AN:

152310

Hom.:

Cov.:

AF XY:

0.00608

AC XY:

453

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.0227

AC:

942

AN:

41582

American (AMR)

AF:

0.00314

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68014

Other (OTH)

AF:

0.00426

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

107

160

214

267

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.00471

Hom.:

Bravo

AF:

0.00750

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Autosomal dominant nonsyndromic hearing loss 11 (1)

Autosomal recessive nonsyndromic hearing loss 2 (1)

not specified (1)

Usher syndrome type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

1.2

(source)

DANN

Benign

0.71

PhyloP100

2.8

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over