NM_000260.4:c.3086A>G

Variant names:

• chr11-77182132-A-G
• rs60103800
• NM_000260.4:c.3086A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP3 BP4_Strong BP6 BS1 BS2

The NM_000260.4(MYO7A):​c.3086A>G​(p.His1029Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000362 in 1,613,254 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. H1029H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00020 (4 hom.)
• Consequence: MYO7A NM_000260.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:6
• Conservation: PhyloP100: 8.94
• 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 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 -12 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, phyloP100way_vertebrate, PrimateAI, PROVEAN, REVEL, REVEL [when BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.013509989).
• BP6: Variant 11-77182132-A-G is Benign according to our data. Variant chr11-77182132-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 178483.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00195 (296/152130) while in subpopulation AFR AF = 0.00689 (286/41534). AF 95% confidence interval is 0.00623. There are 1 homozygotes in GnomAd4. There are 141 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 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.3086A>G	p.His1029Arg	missense	Exon 24 of 49	NP_000251.3	Q13402-1
	MYO7A	NM_001127180.2		c.3086A>G	p.His1029Arg	missense	Exon 24 of 49	NP_001120652.1	Q13402-2
	MYO7A	NM_001369365.1		c.3053A>G	p.His1018Arg	missense	Exon 25 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.3086A>G	p.His1029Arg	missense	Exon 24 of 49	ENSP00000386331.3	Q13402-1
	MYO7A	ENST00000458637.6	TSL:1	c.3086A>G	p.His1029Arg	missense	Exon 24 of 49	ENSP00000392185.2	Q13402-2
	MYO7A	ENST00000409619.6	TSL:1	c.3053A>G	p.His1018Arg	missense	Exon 25 of 50	ENSP00000386635.2	Q13402-8

Frequencies

GnomAD3 genomes AF: 0.00195 AC: 297 AN: 152012 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00693

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000960

GnomAD2 exomes AF: 0.000564 AC: 140 AN: 248092 AF XY: 0.000430

Gnomad AFR exome AF: 0.00809

Gnomad AMR exome AF: 0.000377

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000197 AC: 288 AN: 1461124 Hom.: 4 Cov.: 33 AF XY: 0.000179 AC XY: 130 AN XY: 726846

African (AFR) AF: 0.00726 AC: 243 AN: 33480

American (AMR) AF: 0.000358 AC: 16 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52844

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111850

Other (OTH) AF: 0.000381 AC: 23 AN: 60366

GnomAD4 genome AF: 0.00195 AC: 296 AN: 152130 Hom.: 1 Cov.: 31 AF XY: 0.00190 AC XY: 141 AN XY: 74374

African (AFR) AF: 0.00689 AC: 286 AN: 41534

American (AMR) AF: 0.000523 AC: 8 AN: 15290

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10576

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67968

Other (OTH) AF: 0.000950 AC: 2 AN: 2106

Alfa AF: 0.000946 Hom.: 1

Bravo AF: 0.00205

ESP6500AA AF: 0.00427 AC: 18

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000719 AC: 87

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	2	not specified (2)
-	-	1	Autosomal dominant nonsyndromic hearing loss 11 (1)
-	1	-	Autosomal recessive nonsyndromic hearing loss 2 (1)
-	-	1	MYO7A-related disorder (1)
-	1	-	Usher syndrome type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Benign	-0.041	T
BayesDel_noAF	Pathogenic	0.17
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.75	D
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.014	T
MetaSVM	Uncertain	0.31	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		8.9
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-5.1	D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.025	D
Sift4G	Benign	0.097	T
Polyphen		0.27	B
Vest4		0.67
MVP		0.94
MPC		0.23
ClinPred		0.094	T
GERP RS		5.3
Varity_R		0.56
gMVP		0.77
Mutation Taster		=22/78	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: rs60103800; hg19: chr11-76893178; COSMIC: COSV101289114; COSMIC: COSV101289114;