11-77194346-C-T

Variant names:

• chr11-77194346-C-T
• rs143216377
• NM_000260.4:c.4153-8C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_000260.4(MYO7A):​c.4153-8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,609,654 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00063 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (1 hom.)
• Consequence: MYO7A NM_000260.4 splice_region, intron
• Scores: Splicing: ADA: 0.00005476
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: 0.697
• Publications: 0 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 11-77194346-C-T is Benign according to our data. Variant chr11-77194346-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 178485.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.00109 (1583/1457480) while in subpopulation NFE AF = 0.00133 (1481/1110160). AF 95% confidence interval is 0.00128. There are 1 homozygotes in GnomAdExome4. There are 725 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO7A	NM_000260.4	c.4153-8C>T		splice_region_variant, intron_variant	Intron 31 of 48	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.4153-8C>T		splice_region_variant, intron_variant	Intron 31 of 48	1	NM_000260.4	ENSP00000386331.3
MYO7A	ENST00000458637.6	c.4153-8C>T		splice_region_variant, intron_variant	Intron 31 of 48	1		ENSP00000392185.2
MYO7A	ENST00000409619.6	c.4120-8C>T		splice_region_variant, intron_variant	Intron 32 of 49	1		ENSP00000386635.2
MYO7A	ENST00000458169.2	c.1696-8C>T		splice_region_variant, intron_variant	Intron 11 of 28	1		ENSP00000417017.2
MYO7A	ENST00000670577.1	n.1993-8C>T		splice_region_variant, intron_variant	Intron 14 of 31			ENSP00000499323.1

Frequencies

GnomAD3 genomes AF: 0.000631 AC: 96 AN: 152174 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000265

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: 0.00119

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000418 AC: 101 AN: 241786 AF XY: 0.000374

Gnomad AFR exome AF: 0.000205

Gnomad AMR exome AF: 0.0000295

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000849

Gnomad OTH exome AF: 0.000509

GnomAD4 exome AF: 0.00109 AC: 1583 AN: 1457480 Hom.: 1 Cov.: 30 AF XY: 0.00100 AC XY: 725 AN XY: 724530

African (AFR) AF: 0.000180 AC: 6 AN: 33400

American (AMR) AF: 0.0000904 AC: 4 AN: 44260

Ashkenazi Jewish (ASJ) AF: 0.0000385 AC: 1 AN: 25970

East Asian (EAS) AF: 0.00 AC: 0 AN: 39562

South Asian (SAS) AF: 0.0000235 AC: 2 AN: 85168

European-Finnish (FIN) AF: 0.0000189 AC: 1 AN: 53004

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00133 AC: 1481 AN: 1110160

Other (OTH) AF: 0.00146 AC: 88 AN: 60204

GnomAD4 genome AF: 0.000631 AC: 96 AN: 152174 Hom.: 0 Cov.: 33 AF XY: 0.000511 AC XY: 38 AN XY: 74344

African (AFR) AF: 0.000265 AC: 11 AN: 41452

American (AMR) AF: 0.000262 AC: 4 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00119 AC: 81 AN: 67990

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000358 Hom.: 0

Bravo AF: 0.000623

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Feb 22, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MYO7A: BP4 -

Autosomal recessive nonsyndromic hearing loss 2 Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Usher syndrome type 1 Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:1

Aug 19, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

4153-8C>T in intron 31 of MYO7A: This variant is not expected to have clinical s ignificance because a C>T change at this position does not diverge from the spli ce consensus sequence and is therefore unlikely to impact splicing. It has been identified in 0.12% (10/8348) of European American chromosomes and 0.074% (3/403 6) of African American chromosomes by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS/; dbSNP rs143216377). -

Autosomal dominant nonsyndromic hearing loss 11 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	2.3
DANN	Benign	0.62
PhyloP100		0.70
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000055
dbscSNV1_RF	Benign	0.0060
SpliceAI score (max)		0.010		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: rs143216377; hg19: chr11-76905391;