rs111033503

Variant names:

• chr11-77157263-G-GTGCCCACATTTT
• rs111033503
• NM_000260.4:c.736-15_736-4dupTGCCCACATTTT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000260.4(MYO7A):​c.736-15_736-4dupTGCCCACATTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00366 in 1,591,982 control chromosomes in the GnomAD database, including 137 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (79 hom., cov: 33)
  • Exomes 𝑓: 0.0022 (58 hom.)
• Consequence: MYO7A NM_000260.4 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.25
• 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 -16 ACMG points.

• BP6: Variant 11-77157263-G-GTGCCCACATTTT is Benign according to our data. Variant chr11-77157263-G-GTGCCCACATTTT is described in ClinVar as Benign. ClinVar VariationId is 43342.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0571 is higher than 0.05.

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.736-15_736-4dupTGCCCACATTTT		splice_region intron	N/A	NP_000251.3
	MYO7A	NM_001127180.2		c.736-15_736-4dupTGCCCACATTTT		splice_region intron	N/A	NP_001120652.1
	MYO7A	NM_001369365.1		c.703-15_703-4dupTGCCCACATTTT		splice_region 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.736-16_736-15insTGCCCACATTTT		intron	N/A	ENSP00000386331.3
	MYO7A	ENST00000458637.6	TSL:1	c.736-16_736-15insTGCCCACATTTT		intron	N/A	ENSP00000392185.2
	MYO7A	ENST00000409619.6	TSL:1	c.703-16_703-15insTGCCCACATTTT		intron	N/A	ENSP00000386635.2

Frequencies

GnomAD3 genomes AF: 0.0176 AC: 2674 AN: 152204 Hom.: 79 Cov.: 33

Gnomad AFR AF: 0.0588

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00766

Gnomad ASJ AF: 0.0176

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.0120

GnomAD2 exomes AF: 0.00431 AC: 973 AN: 225834 AF XY: 0.00321

Gnomad AFR exome AF: 0.0508

Gnomad AMR exome AF: 0.00335

Gnomad ASJ exome AF: 0.0154

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000522

Gnomad OTH exome AF: 0.00334

GnomAD4 exome AF: 0.00218 AC: 3139 AN: 1439660 Hom.: 58 Cov.: 29 AF XY: 0.00188 AC XY: 1345 AN XY: 715366

African (AFR) AF: 0.0588 AC: 1919 AN: 32620

American (AMR) AF: 0.00409 AC: 172 AN: 42094

Ashkenazi Jewish (ASJ) AF: 0.0145 AC: 375 AN: 25860

East Asian (EAS) AF: 0.00 AC: 0 AN: 39094

South Asian (SAS) AF: 0.000131 AC: 11 AN: 83810

European-Finnish (FIN) AF: 0.0000190 AC: 1 AN: 52556

Middle Eastern (MID) AF: 0.00349 AC: 20 AN: 5738

European-Non Finnish (NFE) AF: 0.000277 AC: 304 AN: 1098204

Other (OTH) AF: 0.00565 AC: 337 AN: 59684

GnomAD4 genome AF: 0.0177 AC: 2690 AN: 152322 Hom.: 79 Cov.: 33 AF XY: 0.0173 AC XY: 1287 AN XY: 74488

African (AFR) AF: 0.0590 AC: 2454 AN: 41560

American (AMR) AF: 0.00765 AC: 117 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0176 AC: 61 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000426 AC: 29 AN: 68032

Other (OTH) AF: 0.0118 AC: 25 AN: 2114

Alfa AF: 0.0120 Hom.: 7

Asia WGS AF: 0.00577 AC: 20 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs111033503; hg19: chr11-76868309;