rs12420129

Variant names:

• chr11-77156089-C-T
• rs12420129
• NM_000260.4:c.468C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BA1

The NM_000260.4(MYO7A):​c.468C>T​(p.Ile156Ile) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.026 in 1,613,478 control chromosomes in the GnomAD database, including 1,402 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★★). The gene MYO7A is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.031 (209 hom., cov: 33)
  • Exomes 𝑓: 0.025 (1193 hom.)
• Consequence: MYO7A NM_000260.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.9918
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 2.73
• Publications: 7 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

Specifications for MYO7A are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -15 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BP6: Variant 11-77156089-C-T is Benign according to our data. Variant chr11-77156089-C-T is described in ClinVar as Benign. ClinVar VariationId is 43252.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.113 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.468C>T	p.Ile156Ile	splice_region synonymous	Exon 5 of 49	NP_000251.3	Q13402-1
	MYO7A	NM_001127180.2		c.468C>T	p.Ile156Ile	splice_region synonymous	Exon 5 of 49	NP_001120652.1	Q13402-2
	MYO7A	NM_001369365.1		c.435C>T	p.Ile145Ile	splice_region synonymous	Exon 6 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.468C>T	p.Ile156Ile	splice_region synonymous	Exon 5 of 49	ENSP00000386331.3	Q13402-1
	MYO7A	ENST00000458637.6	TSL:1	c.468C>T	p.Ile156Ile	splice_region synonymous	Exon 5 of 49	ENSP00000392185.2	Q13402-2
	MYO7A	ENST00000409619.6	TSL:1	c.435C>T	p.Ile145Ile	splice_region synonymous	Exon 6 of 50	ENSP00000386635.2	Q13402-8

Frequencies

GnomAD3 genomes AF: 0.0308 AC: 4686 AN: 152224 Hom.: 209 Cov.: 33

Gnomad AFR AF: 0.00545

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.118

Gnomad ASJ AF: 0.00779

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.0120

Gnomad FIN AF: 0.0964

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0216

Gnomad OTH AF: 0.0301

GnomAD2 exomes AF: 0.0455 AC: 11310 AN: 248320 AF XY: 0.0388

Gnomad AFR exome AF: 0.00518

Gnomad AMR exome AF: 0.179

Gnomad ASJ exome AF: 0.00786

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.0947

Gnomad NFE exome AF: 0.0208

Gnomad OTH exome AF: 0.0414

GnomAD4 exome AF: 0.0255 AC: 37188 AN: 1461136 Hom.: 1193 Cov.: 31 AF XY: 0.0242 AC XY: 17570 AN XY: 726798

African (AFR) AF: 0.00412 AC: 138 AN: 33478

American (AMR) AF: 0.174 AC: 7771 AN: 44614

Ashkenazi Jewish (ASJ) AF: 0.00750 AC: 196 AN: 26136

East Asian (EAS) AF: 0.000680 AC: 27 AN: 39696

South Asian (SAS) AF: 0.0134 AC: 1155 AN: 86174

European-Finnish (FIN) AF: 0.0939 AC: 4993 AN: 53162

Middle Eastern (MID) AF: 0.00763 AC: 44 AN: 5768

European-Non Finnish (NFE) AF: 0.0194 AC: 21552 AN: 1111748

Other (OTH) AF: 0.0217 AC: 1312 AN: 60360

GnomAD4 genome AF: 0.0308 AC: 4690 AN: 152342 Hom.: 209 Cov.: 33 AF XY: 0.0354 AC XY: 2637 AN XY: 74494

African (AFR) AF: 0.00544 AC: 226 AN: 41578

American (AMR) AF: 0.118 AC: 1805 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00779 AC: 27 AN: 3468

East Asian (EAS) AF: 0.00231 AC: 12 AN: 5190

South Asian (SAS) AF: 0.0120 AC: 58 AN: 4834

European-Finnish (FIN) AF: 0.0964 AC: 1023 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0216 AC: 1472 AN: 68032

Other (OTH) AF: 0.0298 AC: 63 AN: 2116

Alfa AF: 0.0236 Hom.: 169

Bravo AF: 0.0323

Asia WGS AF: 0.0120 AC: 43 AN: 3478

EpiCase AF: 0.0178

EpiControl AF: 0.0163

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)
-	-	1	Autosomal recessive nonsyndromic hearing loss 2 (1)
-	-	1	Usher syndrome type 1 (1)
-	-	1	Usher syndrome type 1B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.19
CADD	Benign	19
DANN	Benign	0.93
PhyloP100		2.7
Mutation Taster		=33/67	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.87
SpliceAI score (max)		0.030		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: rs12420129; hg19: chr11-76867135;