NM_000260.4:c.5156A>G

Variant names:

• chr11-77202412-A-G
• rs77625410
• NM_000260.4:c.5156A>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_000260.4(MYO7A):​c.5156A>G​(p.Tyr1719Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0153 in 1,552,260 control chromosomes in the GnomAD database, including 770 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.045 (369 hom., cov: 32)
  • Exomes 𝑓: 0.012 (401 hom.)
• Consequence: MYO7A NM_000260.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 8.81
• Publications: 20 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: Benign. The variant received -18 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=0.002670139).
• BP6: Variant 11-77202412-A-G is Benign according to our data. Variant chr11-77202412-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 43274.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.13 is higher than 0.05.

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.5156A>G	p.Tyr1719Cys	missense	Exon 37 of 49	NP_000251.3	Q13402-1
	MYO7A	NM_001127180.2		c.5042A>G	p.Tyr1681Cys	missense	Exon 37 of 49	NP_001120652.1	Q13402-2
	MYO7A	NM_001369365.1		c.5009A>G	p.Tyr1670Cys	missense	Exon 38 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.5156A>G	p.Tyr1719Cys	missense	Exon 37 of 49	ENSP00000386331.3	Q13402-1
	MYO7A	ENST00000458637.6	TSL:1	c.5042A>G	p.Tyr1681Cys	missense	Exon 37 of 49	ENSP00000392185.2	Q13402-2
	MYO7A	ENST00000409619.6	TSL:1	c.5009A>G	p.Tyr1670Cys	missense	Exon 38 of 50	ENSP00000386635.2	Q13402-8

Frequencies

GnomAD3 genomes AF: 0.0449 AC: 6829 AN: 152074 Hom.: 360 Cov.: 32

Gnomad AFR AF: 0.133

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0260

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00851

Gnomad FIN AF: 0.00650

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0101

Gnomad OTH AF: 0.0403

GnomAD2 exomes AF: 0.0161 AC: 2528 AN: 157078 AF XY: 0.0139

Gnomad AFR exome AF: 0.128

Gnomad AMR exome AF: 0.0170

Gnomad ASJ exome AF: 0.0134

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00523

Gnomad NFE exome AF: 0.0103

Gnomad OTH exome AF: 0.0177

GnomAD4 exome AF: 0.0121 AC: 16918 AN: 1400068 Hom.: 401 Cov.: 31 AF XY: 0.0117 AC XY: 8103 AN XY: 690672

African (AFR) AF: 0.134 AC: 4245 AN: 31708

American (AMR) AF: 0.0184 AC: 659 AN: 35830

Ashkenazi Jewish (ASJ) AF: 0.0123 AC: 309 AN: 25170

East Asian (EAS) AF: 0.0000279 AC: 1 AN: 35854

South Asian (SAS) AF: 0.00716 AC: 568 AN: 79288

European-Finnish (FIN) AF: 0.00535 AC: 262 AN: 48972

Middle Eastern (MID) AF: 0.0224 AC: 127 AN: 5668

European-Non Finnish (NFE) AF: 0.00894 AC: 9649 AN: 1079542

Other (OTH) AF: 0.0189 AC: 1098 AN: 58036

GnomAD4 genome AF: 0.0451 AC: 6871 AN: 152192 Hom.: 369 Cov.: 32 AF XY: 0.0431 AC XY: 3206 AN XY: 74408

African (AFR) AF: 0.133 AC: 5528 AN: 41512

American (AMR) AF: 0.0260 AC: 397 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0118 AC: 41 AN: 3468

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5158

South Asian (SAS) AF: 0.00852 AC: 41 AN: 4814

European-Finnish (FIN) AF: 0.00650 AC: 69 AN: 10616

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0101 AC: 689 AN: 68018

Other (OTH) AF: 0.0399 AC: 84 AN: 2106

Alfa AF: 0.0192 Hom.: 371

Bravo AF: 0.0499

TwinsUK AF: 0.00917 AC: 34

ALSPAC AF: 0.0101 AC: 39

ESP6500AA AF: 0.111 AC: 448

ESP6500EA AF: 0.00896 AC: 74

ExAC AF: 0.0109 AC: 1117

Asia WGS AF: 0.0130 AC: 47 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	2	Usher syndrome type 1 (2)
-	-	1	Autosomal dominant nonsyndromic hearing loss 11 (1)
-	-	1	Autosomal recessive nonsyndromic hearing loss 2 (1)
-	-	1	Retinal dystrophy (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	0.32
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		8.8
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-4.1	D
REVEL	Uncertain	0.49
Sift	Benign	0.056	T
Sift4G	Benign	0.16	T
Polyphen		0.90	P
Vest4		0.83
MPC		0.48
ClinPred		0.016	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.46
gMVP		0.60
Mutation Taster		=80/20	polymorphism (auto)

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: rs77625410; hg19: chr11-76913457;