rs111033388

chr11-77214658-G-GCCATGAGCAAACAGCGGGGCT

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 3P and 16B. PM4 PP3 BP6_Very_Strong BS1 BS2

The NM_000260.4(MYO7A):c.6614_6634dup(p.Met2205_Ser2211dup) variant causes a inframe insertion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00126 in 1,589,124 control chromosomes in the GnomAD database, including 30 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0070 (19 hom., cov: 32)
  • Exomes 𝑓: 0.00065 (11 hom.)
• Consequence: MYO7A NM_000260.4 inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 7.53

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_000260.4.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• BP6: Variant 11-77214658-G-GCCATGAGCAAACAGCGGGGCT is Benign according to our data. Variant chr11-77214658-G-GCCATGAGCAAACAGCGGGGCT is described in ClinVar as [Likely_benign]. Clinvar id is 177815.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 = 0.00696 (1060/152304) while in subpopulation AFR AF= 0.0245 (1018/41538). AF 95% confidence interval is 0.0233. There are 19 homozygotes in gnomad4. There are 488 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO7A	NM_000260.4	c.6614_6634dup	p.Met2205_Ser2211dup	inframe_insertion	49/49	ENST00000409709.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO7A	ENST00000409709.9	c.6614_6634dup	p.Met2205_Ser2211dup	inframe_insertion	49/49	1	NM_000260.4

Frequencies

GnomAD3 genomes AF: 0.00698 AC: 1062 AN: 152186 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.0246

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: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00116 AC: 244 AN: 210546 Hom.: 2 AF XY: 0.000965 AC XY: 109 AN XY: 112914

Gnomad AFR exome AF: 0.0170

Gnomad AMR exome AF: 0.00103

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000390

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000428

Gnomad OTH exome AF: 0.000557

GnomAD4 exome AF: 0.000651 AC: 936 AN: 1436820 Hom.: 11 Cov.: 30 AF XY: 0.000563 AC XY: 401 AN XY: 711950

Gnomad4 AFR exome AF: 0.0240

Gnomad4 AMR exome AF: 0.00113

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000244

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000127

Gnomad4 OTH exome AF: 0.00131

GnomAD4 genome AF: 0.00696 AC: 1060 AN: 152304 Hom.: 19 Cov.: 32 AF XY: 0.00655 AC XY: 488 AN XY: 74478

Gnomad4 AFR AF: 0.0245

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00331 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 24, 2022	See Variant Classification Assertion Criteria. -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 28, 2016	c.6614_6634dup (p.Met2205_Ser221dup) in exon49 of MYO7A: This variant is not exp ected to have clinical significance because it has been identified in 2% (73/340 2) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac .broadinstitute.org; dbSNP rs111033388). -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs111033388; hg19: chr11-76925703;