dbSNP rs111033287: MYO7A:p.Arg1743Arg (chr11-77203118-C-A) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4BP6BP7BS1BS2

The NM_000260.4(MYO7A):c.5227C>A(p.Arg1743Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000197 in 1,549,698 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00082 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00013 ( 2 hom. )

Consequence

MYO7A
NM_000260.4 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 0.852

Publications

15 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

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.13).

BP6

Variant 11-77203118-C-A is Benign according to our data. Variant chr11-77203118-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 286095.

BP7

Synonymous conserved (PhyloP=0.852 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00082 (125/152354) while in subpopulation AFR AF = 0.00286 (119/41584). AF 95% confidence interval is 0.00244. There are 0 homozygotes in GnomAd4. There are 62 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 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	HGVSp	Effect	Exon Rank	Protein	UniProt
MYO7A	NM_000260.4	MANE Select	c.5227C>A	p.Arg1743Arg	synonymous	Exon 38 of 49	NP_000251.3	Q13402-1
MYO7A	NM_001127180.2		c.5113C>A	p.Arg1705Arg	synonymous	Exon 38 of 49	NP_001120652.1	Q13402-2
MYO7A	NM_001369365.1		c.5080C>A	p.Arg1694Arg	synonymous	Exon 39 of 50	NP_001356294.1	Q13402-8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MYO7A	ENST00000409709.9	TSL:1 MANE Select	c.5227C>A	p.Arg1743Arg	synonymous	Exon 38 of 49	ENSP00000386331.3	Q13402-1
MYO7A	ENST00000458637.6	TSL:1	c.5113C>A	p.Arg1705Arg	synonymous	Exon 38 of 49	ENSP00000392185.2	Q13402-2
MYO7A	ENST00000409619.6	TSL:1	c.5080C>A	p.Arg1694Arg	synonymous	Exon 39 of 50	ENSP00000386635.2	Q13402-8

Frequencies

GnomAD3 genomes

AF:

0.000775

AC:

118

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00270

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

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:

0.000280

AC:

AN:

153820

AF XY:

0.000244

show subpopulations

Gnomad AFR exome

AF:

0.00447

Gnomad AMR exome

AF:

0.000243

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000168

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000129

AC:

180

AN:

1397344

Hom.:

Cov.:

AF XY:

0.000113

AC XY:

AN XY:

689314

show subpopulations

African (AFR)

AF:

0.00402

AC:

127

AN:

31558

American (AMR)

AF:

0.000252

AC:

AN:

35784

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25182

East Asian (EAS)

AF:

0.00

AC:

AN:

35794

South Asian (SAS)

AF:

0.00

AC:

AN:

79174

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48576

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4094

European-Non Finnish (NFE)

AF:

9.26e-7

AC:

AN:

1079332

Other (OTH)

AF:

0.000743

AC:

AN:

57850

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.000820

AC:

125

AN:

152354

Hom.:

Cov.:

AF XY:

0.000832

AC XY:

AN XY:

74506

show subpopulations

African (AFR)

AF:

0.00286

AC:

119

AN:

41584

American (AMR)

AF:

0.000261

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00000813

Hom.:

Bravo

AF:

0.000910

Asia WGS

AF:

0.00173

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)

MYO7A-related disorder (1)

not specified (1)

Usher syndrome type 1B (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.13

CADD

Benign

9.4

(source)

DANN

Benign

0.71

PhyloP100

0.85

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

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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