Genetic Variant MYO7A:c.1798-15C>T (chr11-77172733-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000260.4(MYO7A):c.1798-15C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00144 in 1,550,924 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0074 ( 18 hom., cov: 33)

Exomes 𝑓: 0.00080 ( 12 hom. )

Consequence

MYO7A
NM_000260.4 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.208

Publications

1 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, 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

MYO7A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 11-77172733-C-T is Benign according to our data. Variant chr11-77172733-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 178624.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00739 (1125/152334) while in subpopulation AFR AF = 0.0259 (1078/41578). AF 95% confidence interval is 0.0246. There are 18 homozygotes in GnomAd4. There are 541 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 18 AD,AR 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
MYO7A	NM_000260.4	MANE Select	c.1798-15C>T	intron	N/A	NP_000251.3
MYO7A	NM_001127180.2		c.1798-15C>T	intron	N/A	NP_001120652.1
MYO7A	NM_001369365.1		c.1765-15C>T	intron	N/A	NP_001356294.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
MYO7A	ENST00000409709.9	TSL:1 MANE Select	c.1798-15C>T	intron	N/A	ENSP00000386331.3
MYO7A	ENST00000458637.6	TSL:1	c.1798-15C>T	intron	N/A	ENSP00000392185.2
MYO7A	ENST00000409619.6	TSL:1	c.1765-15C>T	intron	N/A	ENSP00000386635.2

Frequencies

GnomAD3 genomes

AF:

0.00738

AC:

1123

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0260

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00183

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00178

AC:

276

AN:

155418

AF XY:

0.00156

show subpopulations

Gnomad AFR exome

AF:

0.0300

Gnomad AMR exome

AF:

0.00104

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000904

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000824

Gnomad OTH exome

AF:

0.000690

GnomAD4 exome

AF:

0.000797

AC:

1115

AN:

1398590

Hom.:

Cov.:

AF XY:

0.000698

AC XY:

482

AN XY:

690158

show subpopulations

African (AFR)

AF:

0.0272

AC:

859

AN:

31636

American (AMR)

AF:

0.00128

AC:

AN:

36026

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25192

East Asian (EAS)

AF:

0.0000279

AC:

AN:

35846

South Asian (SAS)

AF:

0.000240

AC:

AN:

79216

European-Finnish (FIN)

AF:

0.0000209

AC:

AN:

47894

Middle Eastern (MID)

AF:

0.00110

AC:

AN:

4554

European-Non Finnish (NFE)

AF:

0.0000741

AC:

AN:

1080286

Other (OTH)

AF:

0.00179

AC:

104

AN:

57940

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

125

188

250

313

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

150

<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:

0.00739

AC:

1125

AN:

152334

Hom.:

Cov.:

AF XY:

0.00726

AC XY:

541

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.0259

AC:

1078

AN:

41578

American (AMR)

AF:

0.00183

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000176

AC:

AN:

68018

Other (OTH)

AF:

0.00284

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

119

178

238

297

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00920

Hom.:

Bravo

AF:

0.00836

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

4.9

(source)

DANN

Benign

0.76

PhyloP100

0.21

Mutation Taster

=99/1

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

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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