chr11-77198633-C-G

Variant names:

• chr11-77198633-C-G
• rs72933642
• NM_000260.4:c.4568+12C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000260.4(MYO7A):​c.4568+12C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00669 in 1,613,342 control chromosomes in the GnomAD database, including 192 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0091 (47 hom., cov: 33)
  • Exomes 𝑓: 0.0064 (145 hom.)
• Consequence: MYO7A NM_000260.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.239
• Publications: 1 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 11-77198633-C-G is Benign according to our data. Variant chr11-77198633-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 43246.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00915 (1393/152308) while in subpopulation EAS AF = 0.0133 (69/5182). AF 95% confidence interval is 0.0108. There are 47 homozygotes in GnomAd4. There are 939 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 47 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO7A	NM_000260.4	MANE Select	c.4568+12C>G		intron	N/A	NP_000251.3
	MYO7A	NM_001127180.2		c.4568+12C>G		intron	N/A	NP_001120652.1
	MYO7A	NM_001369365.1		c.4535+12C>G		intron	N/A	NP_001356294.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO7A	ENST00000409709.9	TSL:1 MANE Select	c.4568+12C>G		intron	N/A	ENSP00000386331.3
	MYO7A	ENST00000458637.6	TSL:1	c.4568+12C>G		intron	N/A	ENSP00000392185.2
	MYO7A	ENST00000409619.6	TSL:1	c.4535+12C>G		intron	N/A	ENSP00000386635.2

Frequencies

GnomAD3 genomes AF: 0.00916 AC: 1394 AN: 152192 Hom.: 47 Cov.: 33

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.0135

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.0882

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00489

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.0107 AC: 2649 AN: 247750 AF XY: 0.0106

Gnomad AFR exome AF: 0.000652

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.00140

Gnomad EAS exome AF: 0.0136

Gnomad FIN exome AF: 0.0794

Gnomad NFE exome AF: 0.00476

Gnomad OTH exome AF: 0.00847

GnomAD4 exome AF: 0.00644 AC: 9403 AN: 1461034 Hom.: 145 Cov.: 31 AF XY: 0.00624 AC XY: 4532 AN XY: 726754

African (AFR) AF: 0.000448 AC: 15 AN: 33470

American (AMR) AF: 0.00114 AC: 51 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.00126 AC: 33 AN: 26126

East Asian (EAS) AF: 0.0100 AC: 398 AN: 39692

South Asian (SAS) AF: 0.00280 AC: 241 AN: 86170

European-Finnish (FIN) AF: 0.0704 AC: 3739 AN: 53104

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5754

European-Non Finnish (NFE) AF: 0.00413 AC: 4593 AN: 1111692

Other (OTH) AF: 0.00539 AC: 325 AN: 60350

GnomAD4 genome AF: 0.00915 AC: 1393 AN: 152308 Hom.: 47 Cov.: 33 AF XY: 0.0126 AC XY: 939 AN XY: 74468

African (AFR) AF: 0.000433 AC: 18 AN: 41574

American (AMR) AF: 0.000850 AC: 13 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3468

East Asian (EAS) AF: 0.0133 AC: 69 AN: 5182

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4824

European-Finnish (FIN) AF: 0.0882 AC: 936 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00489 AC: 333 AN: 68034

Other (OTH) AF: 0.00332 AC: 7 AN: 2110

Alfa AF: 0.00371 Hom.: 1

Bravo AF: 0.00307

Asia WGS AF: 0.00895 AC: 31 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Autosomal dominant nonsyndromic hearing loss 11 (1)
-	-	1	Autosomal recessive nonsyndromic hearing loss 2 (1)
-	-	1	not specified (1)
-	-	1	Usher syndrome type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	7.7
DANN	Benign	0.66
PhyloP100		0.24
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs72933642; hg19: chr11-76909678;