rs111033391

Variant names:

• chr11-77190144-G-A
• rs111033391
• NM_000260.4:c.3750+5G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-77190144-G-A
• chr11-77190144-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP3 BS1_Supporting

The NM_000260.4(MYO7A):​c.3750+5G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00135 in 1,555,710 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00064 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (1 hom.)
• Consequence: MYO7A NM_000260.4 splice_region, intron
• Scores: Splicing: ADA: 0.9996
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:9
• Conservation: PhyloP100: 0.367

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00143 (2005/1403360) while in subpopulation NFE AF= 0.00174 (1888/1082592). AF 95% confidence interval is 0.00168. There are 1 homozygotes in gnomad4_exome. There are 930 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO7A	NM_000260.4	c.3750+5G>A		splice_region_variant, intron_variant	Intron 29 of 48	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.3750+5G>A		splice_region_variant, intron_variant	Intron 29 of 48	1	NM_000260.4	ENSP00000386331.3
MYO7A	ENST00000458637.6	c.3750+5G>A		splice_region_variant, intron_variant	Intron 29 of 48	1		ENSP00000392185.2
MYO7A	ENST00000409619.6	c.3717+5G>A		splice_region_variant, intron_variant	Intron 30 of 49	1		ENSP00000386635.2
MYO7A	ENST00000458169.2	c.1293+5G>A		splice_region_variant, intron_variant	Intron 9 of 28	1		ENSP00000417017.2
MYO7A	ENST00000670577.1	n.1590+5G>A		splice_region_variant, intron_variant	Intron 12 of 31			ENSP00000499323.1

Frequencies

GnomAD3 genomes AF: 0.000644 AC: 98 AN: 152232 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00106

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000746 AC: 119 AN: 159564 Hom.: 0 AF XY: 0.000623 AC XY: 53 AN XY: 85058

Gnomad AFR exome AF: 0.000232

Gnomad AMR exome AF: 0.000286

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000175

Gnomad SAS exome AF: 0.0000447

Gnomad FIN exome AF: 0.000757

Gnomad NFE exome AF: 0.00144

Gnomad OTH exome AF: 0.000676

GnomAD4 exome AF: 0.00143 AC: 2005 AN: 1403360 Hom.: 1 Cov.: 32 AF XY: 0.00134 AC XY: 930 AN XY: 692896

Gnomad4 AFR exome AF: 0.000126

Gnomad4 AMR exome AF: 0.000195

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000275

Gnomad4 SAS exome AF: 0.0000127

Gnomad4 FIN exome AF: 0.000471

Gnomad4 NFE exome AF: 0.00174

Gnomad4 OTH exome AF: 0.00139

GnomAD4 genome AF: 0.000643 AC: 98 AN: 152350 Hom.: 0 Cov.: 33 AF XY: 0.000671 AC XY: 50 AN XY: 74504

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000659

Gnomad4 NFE AF: 0.00106

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00102 Hom.: 0

Bravo AF: 0.000688

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:5

Jul 21, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 29 of the MYO7A gene. It does not directly change the encoded amino acid sequence of the MYO7A protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs111033391, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individual(s) with deafness (PMID: 34515852). ClinVar contains an entry for this variant (Variation ID: 43220). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Oct 25, 2018

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3750+5 G>A variant in the MYO7A gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is predicted to reduce the quality of the splice donor site in intron 29, and is expected to cause abnormal gene splicing. The c.3750+5 G>A variant is observed in 125/185496 (0.0674%) alleles in large population cohorts (Lek et al., 2016). We interpret c.3750+5G>A as a variant of uncertain significance. -

Dec 22, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS1_supporting -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MYO7A c.3750+5G>A variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs111033391), ClinVar (classified as uncertain significance by four submitters with associated conditions of autosomal dominant and recessive deafness, type 11, and Usher syndrome type 1), and LOVD 3.0. The variant was identified in control databases in 131 of 190936 chromosomes at a frequency of 0.000686 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 97 of 79474 chromosomes (freq: 0.001221), European (Finnish) in 14 of 19312 chromosomes (freq: 0.000725), Other in 3 of 5524 chromosomes (freq: 0.000543), African in 7 of 17338 chromosomes (freq: 0.000404), Latino in 7 of 25308 chromosomes (freq: 0.000277), East Asian in 2 of 12954 chromosomes (freq: 0.000154) and South Asian in 1 of 22384 chromosomes (freq: 0.000045); it was not observed in the Ashkenazi Jewish population. The c.3750+5G>A variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE) predict the loss of the 5’ canonical splice site. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

not specified Uncertain:2

Feb 11, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 17, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3750+5G>A variant in MYO7A has now been identified by our laboratory in 4 individuals with hearing loss, 2 of those also have retinal abnormalities. Howev er, a second variant in MYO7A was not found in any of them. This variant has bee n identified in 0.1% (93/76532) of European chromosomes and 0.07% (125/185496) o f total chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.br oadinstitute.org; dbSNP rs111033391). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic r ole. This variant is located in the 5' splice region. Computational tools sugges t a possible impact to splicing. However, this information is not predictive eno ugh to determine pathogenicity. In summary, the clinical significance of the c.3 750+5G>A variant is uncertain. -

Usher syndrome type 1B Uncertain:1

Apr 16, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Usher syndrome type 1;C1832475:Autosomal dominant nonsyndromic hearing loss 11;C1838701:Autosomal recessive nonsyndromic hearing loss 2 Uncertain:1

Jan 16, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	10
DANN	Benign	0.80

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.77
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.24		Position offset: 3
DS_DL_spliceai		0.21		Position offset: -5

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

Publications

LitVar

Other links and lift over

dbSNP: rs111033391; hg19: chr11-76901189; COSMIC: COSV101289318;