11-77190774-G-A

Variant names:

• chr11-77190774-G-A
• rs78871677
• NM_000260.4:c.3828G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000260.4(MYO7A):​c.3828G>A​(p.Ser1276Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00423 in 1,597,292 control chromosomes in the GnomAD database, including 211 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S1276S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.022 (115 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (96 hom.)
• Consequence: MYO7A NM_000260.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -2.81
• Publications: 3 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 11-77190774-G-A is Benign according to our data. Variant chr11-77190774-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 43225.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.81 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0731 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.3828G>A	p.Ser1276Ser	synonymous	Exon 30 of 49	NP_000251.3	Q13402-1
	MYO7A	NM_001127180.2		c.3828G>A	p.Ser1276Ser	synonymous	Exon 30 of 49	NP_001120652.1	Q13402-2
	MYO7A	NM_001369365.1		c.3795G>A	p.Ser1265Ser	synonymous	Exon 31 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.3828G>A	p.Ser1276Ser	synonymous	Exon 30 of 49	ENSP00000386331.3	Q13402-1
	MYO7A	ENST00000458637.6	TSL:1	c.3828G>A	p.Ser1276Ser	synonymous	Exon 30 of 49	ENSP00000392185.2	Q13402-2
	MYO7A	ENST00000409619.6	TSL:1	c.3795G>A	p.Ser1265Ser	synonymous	Exon 31 of 50	ENSP00000386635.2	Q13402-8

Frequencies

GnomAD3 genomes AF: 0.0219 AC: 3323 AN: 151786 Hom.: 115 Cov.: 32

Gnomad AFR AF: 0.0754

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0102

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.0139

GnomAD2 exomes AF: 0.00504 AC: 1116 AN: 221260 AF XY: 0.00385

Gnomad AFR exome AF: 0.0725

Gnomad AMR exome AF: 0.00435

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000312

Gnomad OTH exome AF: 0.00378

GnomAD4 exome AF: 0.00237 AC: 3422 AN: 1445388 Hom.: 96 Cov.: 31 AF XY: 0.00207 AC XY: 1482 AN XY: 717266

African (AFR) AF: 0.0781 AC: 2582 AN: 33064

American (AMR) AF: 0.00468 AC: 199 AN: 42542

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25758

East Asian (EAS) AF: 0.00 AC: 0 AN: 38890

South Asian (SAS) AF: 0.000205 AC: 17 AN: 83018

European-Finnish (FIN) AF: 0.0000576 AC: 3 AN: 52054

Middle Eastern (MID) AF: 0.00766 AC: 44 AN: 5744

European-Non Finnish (NFE) AF: 0.000239 AC: 264 AN: 1104478

Other (OTH) AF: 0.00523 AC: 313 AN: 59840

GnomAD4 genome AF: 0.0219 AC: 3327 AN: 151904 Hom.: 115 Cov.: 32 AF XY: 0.0212 AC XY: 1573 AN XY: 74214

African (AFR) AF: 0.0753 AC: 3120 AN: 41408

American (AMR) AF: 0.0102 AC: 155 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4780

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

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000294 AC: 20 AN: 67934

Other (OTH) AF: 0.0138 AC: 29 AN: 2106

Alfa AF: 0.00936 Hom.: 37

Bravo AF: 0.0244

Asia WGS AF: 0.00606 AC: 21 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	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 1B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.061
DANN	Benign	0.78
PhyloP100		-2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=78/22	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs78871677; hg19: chr11-76901819;