rs199818783

Variant names:

• chr11-77160214-C-T
• rs199818783
• NM_000260.4:c.1132C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-77160214-C-T
• chr11-77160214-C-A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM1

The NM_000260.4(MYO7A):​c.1132C>T​(p.Arg378Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000276 in 1,581,022 control chromosomes in the GnomAD database, including 1 homozygotes. 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. R378H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00028 (1 hom.)
• Consequence: MYO7A NM_000260.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11 B:1
• Conservation: PhyloP100: 1.28
• Publications: 5 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: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 13 uncertain in NM_000260.4

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.1132C>T	p.Arg378Cys	missense	Exon 11 of 49	NP_000251.3	Q13402-1
	MYO7A	NM_001127180.2		c.1132C>T	p.Arg378Cys	missense	Exon 11 of 49	NP_001120652.1	Q13402-2
	MYO7A	NM_001369365.1		c.1099C>T	p.Arg367Cys	missense	Exon 12 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.1132C>T	p.Arg378Cys	missense	Exon 11 of 49	ENSP00000386331.3	Q13402-1
	MYO7A	ENST00000458637.6	TSL:1	c.1132C>T	p.Arg378Cys	missense	Exon 11 of 49	ENSP00000392185.2	Q13402-2
	MYO7A	ENST00000409619.6	TSL:1	c.1099C>T	p.Arg367Cys	missense	Exon 12 of 50	ENSP00000386635.2	Q13402-8

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000302 AC: 59 AN: 195244 AF XY: 0.000266

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000169

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000646

Gnomad NFE exome AF: 0.000462

Gnomad OTH exome AF: 0.000592

GnomAD4 exome AF: 0.000283 AC: 405 AN: 1428842 Hom.: 1 Cov.: 31 AF XY: 0.000257 AC XY: 182 AN XY: 707576

African (AFR) AF: 0.0000920 AC: 3 AN: 32622

American (AMR) AF: 0.000198 AC: 8 AN: 40408

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25536

East Asian (EAS) AF: 0.00 AC: 0 AN: 37542

South Asian (SAS) AF: 0.0000370 AC: 3 AN: 81050

European-Finnish (FIN) AF: 0.000830 AC: 42 AN: 50610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5672

European-Non Finnish (NFE) AF: 0.000295 AC: 323 AN: 1096230

Other (OTH) AF: 0.000439 AC: 26 AN: 59172

GnomAD4 genome AF: 0.000204 AC: 31 AN: 152180 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74332

African (AFR) AF: 0.0000241 AC: 1 AN: 41462

American (AMR) AF: 0.000196 AC: 3 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

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

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000294 AC: 20 AN: 68014

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.000440 Hom.: 0

Bravo AF: 0.000212

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000359 AC: 3

ExAC AF: 0.000301 AC: 36

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Autosomal dominant nonsyndromic hearing loss 11 (2)
-	2	-	not provided (2)
-	2	-	Retinal dystrophy (2)
-	1	-	Autosomal recessive nonsyndromic hearing loss 2 (1)
-	1	-	MYO7A-related disorder (1)
-	1	-	not specified (1)
-	1	-	Usher syndrome type 1 (1)
-	1	-	Usher syndrome type 1;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	Pathogenic	0.89
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Benign	0.41	N
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.43	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		1.3
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-6.7	D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.88
MVP		0.93
MPC		0.54
ClinPred		0.28	T
GERP RS		4.1
Varity_R		0.82
gMVP		0.77
Mutation Taster		=13/87	disease causing

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: rs199818783; hg19: chr11-76871260;