11-77166086-A-C

Variant names:

• chr11-77166086-A-C
• rs397516287
• NM_000260.4:c.1721A>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_000260.4(MYO7A):​c.1721A>C​(p.His574Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000411 in 1,461,620 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. H574H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: MYO7A NM_000260.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 4.52
• 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 Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• Usher syndrome type 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Usher syndrome type 1B

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• autosomal dominant nonsyndromic hearing loss 11

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.839

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.1721A>C	p.His574Pro	missense	Exon 15 of 49	NP_000251.3	Q13402-1
	MYO7A	NM_001127180.2		c.1721A>C	p.His574Pro	missense	Exon 15 of 49	NP_001120652.1	Q13402-2
	MYO7A	NM_001369365.1		c.1688A>C	p.His563Pro	missense	Exon 16 of 50	NP_001356294.1	Q13402-8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO7A	ENST00000409709.9	TSL:1 MANE Select	c.1721A>C	p.His574Pro	missense	Exon 15 of 49	ENSP00000386331.3	Q13402-1
	MYO7A	ENST00000458637.6	TSL:1	c.1721A>C	p.His574Pro	missense	Exon 15 of 49	ENSP00000392185.2	Q13402-2
	MYO7A	ENST00000409619.6	TSL:1	c.1688A>C	p.His563Pro	missense	Exon 16 of 50	ENSP00000386635.2	Q13402-8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461620 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727082

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111842

Other (OTH) AF: 0.00 AC: 0 AN: 60370

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)
-	1	-	Usher syndrome type 1;C1838701:Autosomal recessive nonsyndromic hearing loss 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.75	D
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	0.35	D
MutationAssessor	Benign	0.44	N
PhyloP100		4.5
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Uncertain	0.63
Sift	Uncertain	0.023	D
Sift4G	Uncertain	0.057	T
Polyphen		0.48	P
Vest4		0.82
MutPred		0.56		Loss of helix (P = 0.079)
MVP		0.92
MPC		0.43
ClinPred		0.98	D
GERP RS		5.5
PromoterAI		0.054	Neutral
Varity_R		0.79
gMVP		0.78
Mutation Taster		=44/56	disease causing

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

Other links and lift over

dbSNP: rs397516287; hg19: chr11-76877132;