rs45629132

Variant names:

• chr11-77159450-G-A
• rs45629132
• NM_000260.4:c.1007G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-77159450-G-A
• chr11-77159450-G-C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BS1_Supporting BP2

This summary comes from the ClinGen Evidence Repository: The c.1007G>A (p.Arg336His) variant in MYO7A is a missense variant predicted to cause a substitution of arginine by histidine at amino acid 336. The highest population minor allele frequency in gnomAD v4.1.0 is 0.00286 (2854/996858) in the non-Finnish European population, including 4 homozygous individuals, at least two of whom were beyond the average age of onset for MYO7A-related Usher syndrome. This frequency is higher than would be expected for an autosomal recessive condition based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (BS1_Supporting). This variant has been reported in individuals with nonsyndromic, mild-moderate hearing loss in whom a second variant was not detected (PMID:23804846) as well as an individual with Usher syndrome but lacking a second variant (PMID:16470552). A patient with Usher syndrome was homozygous for both p.Arg336His and a likely pathogenic/pathogenic variant (BP2; PMID:33363762, ClinVar IDs: 551533). The REVEL computational prediction tool produced a score of 0.734, which is above the threshold necessary to apply PP3. However, after discussion the expert panel decided not to apply PP3 based upon case level and frequency data. In summary, this variant meets criteria to be classified as likely benign for both Usher syndrome and nonsyndromic hearing loss. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BS1_Supporting, BP2. (ClinGen Hearing Loss VCEP specifications version 2; 11.20.2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA132194/MONDO:0019501/005

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 29)
  • Exomes 𝑓: 0.0023 (4 hom.)
• Consequence: MYO7A NM_000260.4 missense
• Clinical Significance: Likely benign reviewed by expert panel U:5 B:11
• Conservation: PhyloP100: 7.72
• Publications: 13 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

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 -2 ACMG points.

• BP2: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: For more information check the summary or visit ClinGen Evidence Repository.

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.1007G>A	p.Arg336His	missense	Exon 10 of 49	NP_000251.3	Q13402-1
	MYO7A	NM_001127180.2		c.1007G>A	p.Arg336His	missense	Exon 10 of 49	NP_001120652.1	Q13402-2
	MYO7A	NM_001369365.1		c.974G>A	p.Arg325His	missense	Exon 11 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.1007G>A	p.Arg336His	missense	Exon 10 of 49	ENSP00000386331.3	Q13402-1
	MYO7A	ENST00000458637.6	TSL:1	c.1007G>A	p.Arg336His	missense	Exon 10 of 49	ENSP00000392185.2	Q13402-2
	MYO7A	ENST00000409619.6	TSL:1	c.974G>A	p.Arg325His	missense	Exon 11 of 50	ENSP00000386635.2	Q13402-8

Frequencies

GnomAD3 genomes AF: 0.00162 AC: 210 AN: 129680 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.000931

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000904

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000245

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000161

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00261

Gnomad OTH AF: 0.000559

GnomAD2 exomes AF: 0.00116 AC: 288 AN: 247514 AF XY: 0.00105

Gnomad AFR exome AF: 0.000713

Gnomad AMR exome AF: 0.000610

Gnomad ASJ exome AF: 0.0000996

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00221

Gnomad OTH exome AF: 0.000830

GnomAD4 exome AF: 0.00234 AC: 2822 AN: 1204636 Hom.: 4 Cov.: 35 AF XY: 0.00230 AC XY: 1372 AN XY: 597724

African (AFR) AF: 0.000556 AC: 15 AN: 26990

American (AMR) AF: 0.000578 AC: 22 AN: 38052

Ashkenazi Jewish (ASJ) AF: 0.000171 AC: 3 AN: 17532

East Asian (EAS) AF: 0.0000423 AC: 1 AN: 23628

South Asian (SAS) AF: 0.0000479 AC: 4 AN: 83448

European-Finnish (FIN) AF: 0.000407 AC: 13 AN: 31938

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4548

European-Non Finnish (NFE) AF: 0.00288 AC: 2690 AN: 933932

Other (OTH) AF: 0.00166 AC: 74 AN: 44568

GnomAD4 genome AF: 0.00162 AC: 210 AN: 129732 Hom.: 0 Cov.: 29 AF XY: 0.00151 AC XY: 92 AN XY: 61010

African (AFR) AF: 0.000930 AC: 33 AN: 35472

American (AMR) AF: 0.000902 AC: 10 AN: 11088

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3304

East Asian (EAS) AF: 0.000246 AC: 1 AN: 4064

South Asian (SAS) AF: 0.00 AC: 0 AN: 3734

European-Finnish (FIN) AF: 0.000161 AC: 1 AN: 6228

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 258

European-Non Finnish (NFE) AF: 0.00261 AC: 164 AN: 62926

Other (OTH) AF: 0.000555 AC: 1 AN: 1802

Alfa AF: 0.00206 Hom.: 2

Bravo AF: 0.00125

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.000508 AC: 2

ESP6500EA AF: 0.00193 AC: 16

ExAC AF: 0.00115 AC: 139

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00175

EpiControl AF: 0.00166

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	1	1	Autosomal dominant nonsyndromic hearing loss 11 (2)
-	-	2	not specified (2)
-	1	1	Usher syndrome type 1 (2)
-	-	1	Autosomal recessive nonsyndromic hearing loss 2 (1)
-	1	-	Meniere disease (1)
-	-	1	MYO7A-related disorder (1)
-	-	1	Usher syndrome (1)
-	1	-	Usher syndrome type 1;C1832475:Autosomal dominant nonsyndromic hearing loss 11;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	0.12
BayesDel_addAF	Uncertain	0.038	T
BayesDel_noAF	Pathogenic	0.28
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.64	D
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.099	T
MetaSVM	Uncertain	0.33	D
MutationAssessor	Benign	0.97	L
PhyloP100		7.7
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-2.3	N
REVEL	Pathogenic	0.73
Sift	Benign	0.069	T
Sift4G	Benign	0.070	T
Polyphen		0.99	D
Vest4		0.83
MVP		0.95
MPC		0.11
ClinPred		0.027	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.67
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs45629132; hg19: chr11-76870496; COSMIC: COSV68684980;