rs41298747

Variant names:

• chr11-77199663-C-T
• rs41298747
• NM_000260.4:c.4697C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-77199663-C-T
• chr11-77199663-C-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000260.4(MYO7A):​c.4697C>T​(p.Thr1566Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00537 in 1,612,946 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1566S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0050 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0054 (29 hom.)
• Consequence: MYO7A NM_000260.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.446
• 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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006384641).
• BP6: Variant 11-77199663-C-T is Benign according to our data. Variant chr11-77199663-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 43254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00502 (764/152328) while in subpopulation NFE AF = 0.00772 (525/68032). AF 95% confidence interval is 0.00717. There are 4 homozygotes in GnomAd4. There are 357 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR gene

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.4697C>T	p.Thr1566Met	missense	Exon 35 of 49	NP_000251.3	Q13402-1
	MYO7A	NM_001127180.2		c.4583C>T	p.Thr1528Met	missense	Exon 35 of 49	NP_001120652.1	Q13402-2
	MYO7A	NM_001369365.1		c.4550C>T	p.Thr1517Met	missense	Exon 36 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.4697C>T	p.Thr1566Met	missense	Exon 35 of 49	ENSP00000386331.3	Q13402-1
	MYO7A	ENST00000458637.6	TSL:1	c.4583C>T	p.Thr1528Met	missense	Exon 35 of 49	ENSP00000392185.2	Q13402-2
	MYO7A	ENST00000409619.6	TSL:1	c.4550C>T	p.Thr1517Met	missense	Exon 36 of 50	ENSP00000386635.2	Q13402-8

Frequencies

GnomAD3 genomes AF: 0.00502 AC: 764 AN: 152212 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.000916

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.0127

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00734

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00772

Gnomad OTH AF: 0.00766

GnomAD2 exomes AF: 0.00499 AC: 1230 AN: 246704 AF XY: 0.00488

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.00239

Gnomad ASJ exome AF: 0.0130

Gnomad EAS exome AF: 0.000278

Gnomad FIN exome AF: 0.00692

Gnomad NFE exome AF: 0.00697

Gnomad OTH exome AF: 0.00651

GnomAD4 exome AF: 0.00540 AC: 7890 AN: 1460618 Hom.: 29 Cov.: 31 AF XY: 0.00536 AC XY: 3893 AN XY: 726520

African (AFR) AF: 0.000687 AC: 23 AN: 33464

American (AMR) AF: 0.00269 AC: 120 AN: 44632

Ashkenazi Jewish (ASJ) AF: 0.0125 AC: 326 AN: 26082

East Asian (EAS) AF: 0.000252 AC: 10 AN: 39692

South Asian (SAS) AF: 0.00125 AC: 108 AN: 86060

European-Finnish (FIN) AF: 0.00601 AC: 318 AN: 52930

Middle Eastern (MID) AF: 0.00919 AC: 53 AN: 5766

European-Non Finnish (NFE) AF: 0.00595 AC: 6617 AN: 1111646

Other (OTH) AF: 0.00522 AC: 315 AN: 60346

GnomAD4 genome AF: 0.00502 AC: 764 AN: 152328 Hom.: 4 Cov.: 33 AF XY: 0.00479 AC XY: 357 AN XY: 74484

African (AFR) AF: 0.000914 AC: 38 AN: 41586

American (AMR) AF: 0.00301 AC: 46 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0127 AC: 44 AN: 3470

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5174

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4826

European-Finnish (FIN) AF: 0.00734 AC: 78 AN: 10626

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00772 AC: 525 AN: 68032

Other (OTH) AF: 0.00758 AC: 16 AN: 2112

Alfa AF: 0.00603 Hom.: 8

Bravo AF: 0.00422

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000958 AC: 4

ESP6500EA AF: 0.00701 AC: 59

ExAC AF: 0.00455 AC: 551

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00703

EpiControl AF: 0.00688

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	Usher syndrome type 1B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	13
DANN	Benign	0.94
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.85	D
MetaRNN	Benign	0.0064	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.45
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.41	N
REVEL	Benign	0.073
Sift	Benign	0.15	T
Sift4G	Benign	0.12	T
Polyphen		0.66	P
Vest4		0.10
MVP		0.75
MPC		0.089
ClinPred		0.0051	T
GERP RS		-1.9
Varity_R		0.017
gMVP		0.13
Mutation Taster		=100/0	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

Other links and lift over

dbSNP: rs41298747; hg19: chr11-76910708; COSMIC: COSV68687502; COSMIC: COSV68687502;