rs727503328

Variant names:

• chr11-77190802-G-A
• rs727503328
• NM_000260.4:c.3856G>A
• MYO7A p.Ala1286Thr

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM1 BP4_Moderate BP6

The NM_000260.4(MYO7A):​c.3856G>A​(p.Ala1286Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000415 in 1,592,094 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1286V) has been classified as Uncertain significance. The gene MYO7A is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000045 (0 hom.)
• Consequence: MYO7A NM_000260.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 4.85
• Publications: 2 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• 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: Ambry Genetics, 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

Specifications for MYO7A are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_000260.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.15894559).
• BP6: Variant 11-77190802-G-A is Benign according to our data. Variant chr11-77190802-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 164692.

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.3856G>A	p.Ala1286Thr	missense	Exon 30 of 49	NP_000251.3	Q13402-1
	MYO7A	NM_001127180.2		c.3856G>A	p.Ala1286Thr	missense	Exon 30 of 49	NP_001120652.1	Q13402-2
	MYO7A	NM_001369365.1		c.3823G>A	p.Ala1275Thr	missense	Exon 31 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.3856G>A	p.Ala1286Thr	missense	Exon 30 of 49	ENSP00000386331.3	Q13402-1
	MYO7A	ENST00000458637.6	TSL:1	c.3856G>A	p.Ala1286Thr	missense	Exon 30 of 49	ENSP00000392185.2	Q13402-2
	MYO7A	ENST00000409619.6	TSL:1	c.3823G>A	p.Ala1275Thr	missense	Exon 31 of 50	ENSP00000386635.2	Q13402-8

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151660 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000606 AC: 13 AN: 214384 AF XY: 0.0000864

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000451 AC: 65 AN: 1440434 Hom.: 0 Cov.: 31 AF XY: 0.0000630 AC XY: 45 AN XY: 714360

African (AFR) AF: 0.0000303 AC: 1 AN: 32952

American (AMR) AF: 0.00 AC: 0 AN: 41670

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25688

East Asian (EAS) AF: 0.0000259 AC: 1 AN: 38618

South Asian (SAS) AF: 0.000644 AC: 53 AN: 82324

European-Finnish (FIN) AF: 0.0000193 AC: 1 AN: 51760

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.00000726 AC: 8 AN: 1101974

Other (OTH) AF: 0.0000168 AC: 1 AN: 59698

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151660 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74018

African (AFR) AF: 0.00 AC: 0 AN: 41224

American (AMR) AF: 0.00 AC: 0 AN: 15200

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10494

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67986

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.0000395 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.42	T
Eigen	Benign	-0.021
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	1.2	L
PhyloP100		4.9
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.30
Sift	Benign	0.33	T
Sift4G	Benign	0.41	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.077
gMVP		0.28
Mutation Taster		=66/34	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs727503328;

hg19: chr11-76901847;

COSMIC: COSV68684663;