rs2276288

Variant names:

• chr11-77201591-A-T
• rs2276288
• NM_000260.4:c.4996A>T

Your query was ambiguous. Multiple possible variants found:

• chr11-77201591-A-T
• chr11-77201591-A-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000260.4(MYO7A):​c.4996A>T​(p.Ser1666Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.548 in 1,613,536 control chromosomes in the GnomAD database, including 246,230 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1666G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.59 (26742 hom., cov: 31)
  • Exomes 𝑓: 0.54 (219488 hom.)
• Consequence: MYO7A NM_000260.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 2.52
• Publications: 51 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=6.6471216E-6).
• BP6: Variant 11-77201591-A-T is Benign according to our data. Variant chr11-77201591-A-T is described in ClinVar as Benign. ClinVar VariationId is 43269.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.681 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.4996A>T	p.Ser1666Cys	missense	Exon 36 of 49	NP_000251.3	Q13402-1
	MYO7A	NM_001127180.2		c.4882A>T	p.Ser1628Cys	missense	Exon 36 of 49	NP_001120652.1	Q13402-2
	MYO7A	NM_001369365.1		c.4849A>T	p.Ser1617Cys	missense	Exon 37 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.4996A>T	p.Ser1666Cys	missense	Exon 36 of 49	ENSP00000386331.3	Q13402-1
	MYO7A	ENST00000458637.6	TSL:1	c.4882A>T	p.Ser1628Cys	missense	Exon 36 of 49	ENSP00000392185.2	Q13402-2
	MYO7A	ENST00000409619.6	TSL:1	c.4849A>T	p.Ser1617Cys	missense	Exon 37 of 50	ENSP00000386635.2	Q13402-8

Frequencies

GnomAD3 genomes AF: 0.587 AC: 89174 AN: 151850 Hom.: 26687 Cov.: 31

Gnomad AFR AF: 0.687

Gnomad AMI AF: 0.487

Gnomad AMR AF: 0.628

Gnomad ASJ AF: 0.441

Gnomad EAS AF: 0.472

Gnomad SAS AF: 0.348

Gnomad FIN AF: 0.627

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.546

Gnomad OTH AF: 0.584

GnomAD2 exomes AF: 0.550 AC: 136951 AN: 249010 AF XY: 0.535

Gnomad AFR exome AF: 0.688

Gnomad AMR exome AF: 0.671

Gnomad ASJ exome AF: 0.445

Gnomad EAS exome AF: 0.488

Gnomad FIN exome AF: 0.627

Gnomad NFE exome AF: 0.550

Gnomad OTH exome AF: 0.524

GnomAD4 exome AF: 0.544 AC: 795340 AN: 1461568 Hom.: 219488 Cov.: 63 AF XY: 0.538 AC XY: 390875 AN XY: 727064

African (AFR) AF: 0.685 AC: 22926 AN: 33480

American (AMR) AF: 0.664 AC: 29693 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.434 AC: 11335 AN: 26134

East Asian (EAS) AF: 0.472 AC: 18756 AN: 39696

South Asian (SAS) AF: 0.372 AC: 32043 AN: 86252

European-Finnish (FIN) AF: 0.625 AC: 33333 AN: 53336

Middle Eastern (MID) AF: 0.446 AC: 2573 AN: 5766

European-Non Finnish (NFE) AF: 0.551 AC: 612747 AN: 1111822

Other (OTH) AF: 0.529 AC: 31934 AN: 60366

GnomAD4 genome AF: 0.588 AC: 89296 AN: 151968 Hom.: 26742 Cov.: 31 AF XY: 0.588 AC XY: 43660 AN XY: 74228

African (AFR) AF: 0.687 AC: 28504 AN: 41474

American (AMR) AF: 0.629 AC: 9613 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.441 AC: 1531 AN: 3468

East Asian (EAS) AF: 0.472 AC: 2421 AN: 5134

South Asian (SAS) AF: 0.348 AC: 1679 AN: 4818

European-Finnish (FIN) AF: 0.627 AC: 6614 AN: 10550

Middle Eastern (MID) AF: 0.490 AC: 144 AN: 294

European-Non Finnish (NFE) AF: 0.546 AC: 37119 AN: 67924

Other (OTH) AF: 0.582 AC: 1228 AN: 2110

Alfa AF: 0.544 Hom.: 17241

Bravo AF: 0.596

TwinsUK AF: 0.562 AC: 2085

ALSPAC AF: 0.552 AC: 2126

ESP6500AA AF: 0.681 AC: 2919

ESP6500EA AF: 0.543 AC: 4591

ExAC AF: 0.543 AC: 65799

Asia WGS AF: 0.435 AC: 1515 AN: 3478

EpiCase AF: 0.541

EpiControl AF: 0.539

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	2	Autosomal dominant nonsyndromic hearing loss 11 (2)
-	-	2	Autosomal recessive nonsyndromic hearing loss 2 (2)
-	-	2	Usher syndrome type 1 (2)
-	-	1	Usher syndrome type 1B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.042
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	17
DANN	Benign	0.078
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.13	T
MetaRNN	Benign	0.0000066	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-1.6	N
PhyloP100		2.5
PrimateAI	Benign	0.40	T
PROVEAN	Benign	5.5	N
REVEL	Benign	0.048
Sift	Benign	1.0	T
Sift4G	Benign	0.86	T
Vest4		0.23
MPC		0.082
ClinPred		0.0031	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.050
gMVP		0.32
Mutation Taster		=94/6	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: rs2276288; hg19: chr11-76912636; COSMIC: COSV68684648; COSMIC: COSV68684648;