11-77184724-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_000260.4(MYO7A):c.3503+9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000137 in 1,553,864 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000076 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00014 (1 hom.)
• Consequence: MYO7A NM_000260.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 1.28

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.066943705).
• BP6: Variant 11-77184724-C-T is Benign according to our data. Variant chr11-77184724-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 505148.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO7A	NM_000260.4	c.3503+9C>T		intron_variant		ENST00000409709.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO7A	ENST00000409709.9	c.3503+9C>T		intron_variant		1	NM_000260.4

Frequencies

GnomAD3 genomes AF: 0.0000757 AC: 9 AN: 118892 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000839

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: 0.000153

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000773 AC: 14 AN: 181006 Hom.: 0 AF XY: 0.0000906 AC XY: 9 AN XY: 99318

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000166

Gnomad OTH exome AF: 0.000217

GnomAD4 exome AF: 0.000142 AC: 204 AN: 1434972 Hom.: 1 Cov.: 31 AF XY: 0.000142 AC XY: 101 AN XY: 712364

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000240

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000256

Gnomad4 SAS exome AF: 0.0000119

Gnomad4 FIN exome AF: 0.0000196

Gnomad4 NFE exome AF: 0.000167

Gnomad4 OTH exome AF: 0.000219

GnomAD4 genome AF: 0.0000757 AC: 9 AN: 118892 Hom.: 0 Cov.: 31 AF XY: 0.0000692 AC XY: 4 AN XY: 57774

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000839

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000153

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000107 Hom.: 0

ExAC AF: 0.0000403 AC: 4

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 11, 2019	In silico analysis, which includes splice predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 23, 2016

p.Pro1171Leu in exon 27A of MYO7A: This variant is not expected to have clinical significance because the proline (Pro) at position 1171 is not conserved in mam mals or evolutionarily distant species with 3 mammals (marmoset, squirrel monkey , Guinea pig) carry a leucine (Leu) at this position. It has also been identifi ed in 2/30018 of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). Of note, the variant results in a missense var iant in only 1 transcript isoform of MYO7A (NM_001127179.2) and lies in an intro nic region in all other transcript isoforms of the gene. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	13
Dann	Benign	0.23
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0096	N
LIST_S2	Benign	0.33	T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.067	T
MetaSVM	Benign	-0.82	T
MutationTaster	Benign	1.0	N;N;N;N
REVEL	Benign	0.077
MVP		0.23
ClinPred		0.071	T
GERP RS		2.4

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

Publications

LitVar

Other links and lift over

dbSNP: rs1481745974; hg19: chr11-76895769;