11-77179873-C-T

Variant names:

• chr11-77179873-C-T
• rs375510570
• NM_000260.4:c.2506C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_000260.4(MYO7A):​c.2506C>T​(p.Arg836Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000343 in 1,540,992 control chromosomes in the GnomAD database, including 1 homozygotes. 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. R836H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00034 (1 hom.)
• Consequence: MYO7A NM_000260.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:2
• Conservation: PhyloP100: 3.27
• 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, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, G2P
• Usher syndrome type 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, PanelApp Australia
• Usher syndrome type 1B

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• autosomal dominant nonsyndromic hearing loss 11

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, PanelApp Australia, 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

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.030988306).
• BP6: Variant 11-77179873-C-T is Benign according to our data. Variant chr11-77179873-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 229003.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO7A	NM_000260.4	MANE Select	c.2506C>T	p.Arg836Cys	missense	Exon 21 of 49	NP_000251.3
	MYO7A	NM_001127180.2		c.2506C>T	p.Arg836Cys	missense	Exon 21 of 49	NP_001120652.1
	MYO7A	NM_001369365.1		c.2473C>T	p.Arg825Cys	missense	Exon 22 of 50	NP_001356294.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO7A	ENST00000409709.9	TSL:1 MANE Select	c.2506C>T	p.Arg836Cys	missense	Exon 21 of 49	ENSP00000386331.3
	MYO7A	ENST00000458637.6	TSL:1	c.2506C>T	p.Arg836Cys	missense	Exon 21 of 49	ENSP00000392185.2
	MYO7A	ENST00000409619.6	TSL:1	c.2473C>T	p.Arg825Cys	missense	Exon 22 of 50	ENSP00000386635.2

Frequencies

GnomAD3 genomes AF: 0.000388 AC: 59 AN: 152254 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000607 AC: 84 AN: 138384 AF XY: 0.000586

Gnomad AFR exome AF: 0.000147

Gnomad AMR exome AF: 0.000327

Gnomad ASJ exome AF: 0.00449

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000113

Gnomad NFE exome AF: 0.000513

Gnomad OTH exome AF: 0.00145

GnomAD4 exome AF: 0.000338 AC: 469 AN: 1388620 Hom.: 1 Cov.: 32 AF XY: 0.000369 AC XY: 253 AN XY: 685284

African (AFR) AF: 0.000158 AC: 5 AN: 31562

American (AMR) AF: 0.000168 AC: 6 AN: 35694

Ashkenazi Jewish (ASJ) AF: 0.00509 AC: 128 AN: 25168

East Asian (EAS) AF: 0.00 AC: 0 AN: 35722

South Asian (SAS) AF: 0.000101 AC: 8 AN: 79160

European-Finnish (FIN) AF: 0.000100 AC: 4 AN: 39848

Middle Eastern (MID) AF: 0.00102 AC: 5 AN: 4910

European-Non Finnish (NFE) AF: 0.000255 AC: 275 AN: 1078738

Other (OTH) AF: 0.000657 AC: 38 AN: 57818

GnomAD4 genome AF: 0.000387 AC: 59 AN: 152372 Hom.: 0 Cov.: 34 AF XY: 0.000362 AC XY: 27 AN XY: 74514

African (AFR) AF: 0.000264 AC: 11 AN: 41590

American (AMR) AF: 0.0000653 AC: 1 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00605 AC: 21 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000382 AC: 26 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00112 Hom.: 0

Bravo AF: 0.000446

ESP6500AA AF: 0.000273 AC: 1

ESP6500EA AF: 0.000546 AC: 4

ExAC AF: 0.000306 AC: 18

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	5	1	not provided (6)
-	-	1	Autosomal dominant nonsyndromic hearing loss 11 (1)
-	1	-	Autosomal recessive nonsyndromic hearing loss 2 (1)
-	1	-	not specified (1)
-	1	-	Usher syndrome type 1 (1)
-	1	-	Usher syndrome type 1B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.039	T
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.77	D
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.031	T
MetaSVM	Uncertain	0.77	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		3.3
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-5.7	D
REVEL	Uncertain	0.60
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.77
MVP		0.94
MPC		0.50
ClinPred		0.095	T
GERP RS		4.4
PromoterAI		-0.015	Neutral
Varity_R		0.81
gMVP		0.64
Mutation Taster		=55/45	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs375510570; hg19: chr11-76890919;