rs142293185

Variant names:

• chr11-77208439-G-A
• rs142293185
• NM_000260.4:c.5866G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000260.4(MYO7A):​c.5866G>A​(p.Val1956Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00416 in 1,612,528 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0037 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0042 (18 hom.)
• Consequence: MYO7A NM_000260.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:12
• Conservation: PhyloP100: 3.89
• Publications: 11 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009595692).
• BP6: Variant 11-77208439-G-A is Benign according to our data. Variant chr11-77208439-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 43305.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0037 (564/152318) while in subpopulation NFE AF = 0.00501 (341/68022). AF 95% confidence interval is 0.00457. There are 2 homozygotes in GnomAd4. There are 260 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.5866G>A	p.Val1956Ile	missense	Exon 43 of 49	NP_000251.3	Q13402-1
	MYO7A	NM_001127180.2		c.5752G>A	p.Val1918Ile	missense	Exon 43 of 49	NP_001120652.1	Q13402-2
	MYO7A	NM_001369365.1		c.5719G>A	p.Val1907Ile	missense	Exon 44 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.5866G>A	p.Val1956Ile	missense	Exon 43 of 49	ENSP00000386331.3	Q13402-1
	MYO7A	ENST00000458637.6	TSL:1	c.5752G>A	p.Val1918Ile	missense	Exon 43 of 49	ENSP00000392185.2	Q13402-2
	MYO7A	ENST00000409619.6	TSL:1	c.5719G>A	p.Val1907Ile	missense	Exon 44 of 50	ENSP00000386635.2	Q13402-8

Frequencies

GnomAD3 genomes AF: 0.00371 AC: 564 AN: 152200 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00399

Gnomad ASJ AF: 0.0167

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.00282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00501

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00398 AC: 987 AN: 248044 AF XY: 0.00400

Gnomad AFR exome AF: 0.00130

Gnomad AMR exome AF: 0.00175

Gnomad ASJ exome AF: 0.0158

Gnomad EAS exome AF: 0.0000558

Gnomad FIN exome AF: 0.00302

Gnomad NFE exome AF: 0.00522

Gnomad OTH exome AF: 0.00481

GnomAD4 exome AF: 0.00421 AC: 6144 AN: 1460210 Hom.: 18 Cov.: 34 AF XY: 0.00415 AC XY: 3015 AN XY: 726398

African (AFR) AF: 0.00126 AC: 42 AN: 33446

American (AMR) AF: 0.00184 AC: 82 AN: 44642

Ashkenazi Jewish (ASJ) AF: 0.0150 AC: 391 AN: 26114

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39688

South Asian (SAS) AF: 0.00203 AC: 175 AN: 86092

European-Finnish (FIN) AF: 0.00341 AC: 182 AN: 53364

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5764

European-Non Finnish (NFE) AF: 0.00452 AC: 5023 AN: 1110768

Other (OTH) AF: 0.00403 AC: 243 AN: 60332

GnomAD4 genome AF: 0.00370 AC: 564 AN: 152318 Hom.: 2 Cov.: 33 AF XY: 0.00349 AC XY: 260 AN XY: 74494

African (AFR) AF: 0.00127 AC: 53 AN: 41572

American (AMR) AF: 0.00399 AC: 61 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0167 AC: 58 AN: 3470

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

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4828

European-Finnish (FIN) AF: 0.00282 AC: 30 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00501 AC: 341 AN: 68022

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.00481 Hom.: 9

Bravo AF: 0.00334

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.00122 AC: 5

ESP6500EA AF: 0.00297 AC: 25

ExAC AF: 0.00432 AC: 523

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00447

EpiControl AF: 0.00452

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	4	not specified (4)
-	-	1	Autosomal dominant nonsyndromic hearing loss 11 (1)
-	1	-	Autosomal recessive nonsyndromic hearing loss 2 (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	Benign	0.14
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T
Eigen	Benign	0.088
Eigen_PC	Benign	0.067
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.0096	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	2.0	M
PhyloP100		3.9
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.82	N
REVEL	Benign	0.24
Sift	Benign	0.24	T
Sift4G	Benign	0.42	T
Polyphen		0.94	P
Vest4		0.37
MVP		0.65
MPC		0.40
ClinPred		0.0082	T
GERP RS		3.4
Varity_R		0.12
gMVP		0.22
Mutation Taster		=76/24	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs142293185; hg19: chr11-76919484;