NM_000260.4:c.2387G>T

Variant names:

• chr11-77179754-G-T
• rs111033224
• NM_000260.4:c.2387G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_000260.4(MYO7A):​c.2387G>T​(p.Arg796Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000431 in 1,392,310 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R796Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: MYO7A NM_000260.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.99
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.861

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO7A	NM_000260.4	c.2387G>T	p.Arg796Leu	missense_variant	Exon 21 of 49	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.2387G>T	p.Arg796Leu	missense_variant	Exon 21 of 49	1	NM_000260.4	ENSP00000386331.3
MYO7A	ENST00000458637.6	c.2387G>T	p.Arg796Leu	missense_variant	Exon 21 of 49	1		ENSP00000392185.2
MYO7A	ENST00000409619.6	c.2354G>T	p.Arg785Leu	missense_variant	Exon 22 of 50	1		ENSP00000386635.2
MYO7A	ENST00000670577.1	n.227G>T		non_coding_transcript_exon_variant	Exon 4 of 32			ENSP00000499323.1
MYO7A	ENST00000458169.2	c.-71G>T		upstream_gene_variant		1		ENSP00000417017.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000431 AC: 6 AN: 1392310 Hom.: 0 Cov.: 31 AF XY: 0.00000437 AC XY: 3 AN XY: 685954

African (AFR) AF: 0.00 AC: 0 AN: 31648

American (AMR) AF: 0.00 AC: 0 AN: 36372

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25090

East Asian (EAS) AF: 0.00 AC: 0 AN: 35844

South Asian (SAS) AF: 0.00 AC: 0 AN: 79242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44144

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5602

European-Non Finnish (NFE) AF: 0.00000557 AC: 6 AN: 1076656

Other (OTH) AF: 0.00 AC: 0 AN: 57712

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D;T;.;.;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D;D;D;D;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D
MetaSVM	Uncertain	0.17	D
MutationAssessor	Uncertain	2.9	M;.;M;.;.
PhyloP100		10
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-6.8	D;.;D;D;.
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D;.;D;D;.
Sift4G	Uncertain	0.0020	D;D;D;D;.
Polyphen		1.0	D;.;.;.;.
Vest4		0.87
MutPred		0.55		Loss of disorder (P = 0.0693);Loss of disorder (P = 0.0693);Loss of disorder (P = 0.0693);.;.;
MVP		0.92
MPC		0.52
ClinPred		1.0	D
GERP RS		5.0
PromoterAI		0.029	Neutral
Varity_R		0.87
gMVP		0.85
Mutation Taster		=8/92	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs111033224; hg19: chr11-76890800;