chr11-77207381-C-T

Variant names:

• chr11-77207381-C-T
• rs111033476
• NM_000260.4:c.5835C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000260.4(MYO7A):​c.5835C>T​(p.Leu1945Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000689 in 1,609,666 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00036 (4 hom.)
• Consequence: MYO7A NM_000260.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.254
• Publications: 1 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, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, G2P
• Usher syndrome type 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, PanelApp Australia
• Usher syndrome type 1B

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• autosomal dominant nonsyndromic hearing loss 11

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 11-77207381-C-T is Benign according to our data. Variant chr11-77207381-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 43302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.254 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0038 (579/152296) while in subpopulation AFR AF = 0.0135 (561/41572). AF 95% confidence interval is 0.0126. There are 0 homozygotes in GnomAd4. There are 261 alleles in the male GnomAd4 subpopulation. Median coverage is 33. 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.5835C>T	p.Leu1945Leu	synonymous	Exon 42 of 49	NP_000251.3
	MYO7A	NM_001127180.2		c.5721C>T	p.Leu1907Leu	synonymous	Exon 42 of 49	NP_001120652.1
	MYO7A	NM_001369365.1		c.5688C>T	p.Leu1896Leu	synonymous	Exon 43 of 50	NP_001356294.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO7A	ENST00000409709.9	TSL:1 MANE Select	c.5835C>T	p.Leu1945Leu	synonymous	Exon 42 of 49	ENSP00000386331.3
	MYO7A	ENST00000458637.6	TSL:1	c.5721C>T	p.Leu1907Leu	synonymous	Exon 42 of 49	ENSP00000392185.2
	MYO7A	ENST00000409619.6	TSL:1	c.5688C>T	p.Leu1896Leu	synonymous	Exon 43 of 50	ENSP00000386635.2

Frequencies

GnomAD3 genomes AF: 0.00379 AC: 577 AN: 152178 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.000806 AC: 194 AN: 240690 AF XY: 0.000667

Gnomad AFR exome AF: 0.0123

Gnomad AMR exome AF: 0.000414

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000918

Gnomad OTH exome AF: 0.000169

GnomAD4 exome AF: 0.000364 AC: 530 AN: 1457370 Hom.: 4 Cov.: 33 AF XY: 0.000308 AC XY: 223 AN XY: 724446

African (AFR) AF: 0.0136 AC: 455 AN: 33400

American (AMR) AF: 0.000407 AC: 18 AN: 44256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26012

East Asian (EAS) AF: 0.0000506 AC: 2 AN: 39546

South Asian (SAS) AF: 0.0000235 AC: 2 AN: 85084

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53136

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5760

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1109938

Other (OTH) AF: 0.000780 AC: 47 AN: 60238

GnomAD4 genome AF: 0.00380 AC: 579 AN: 152296 Hom.: 0 Cov.: 33 AF XY: 0.00350 AC XY: 261 AN XY: 74466

African (AFR) AF: 0.0135 AC: 561 AN: 41572

American (AMR) AF: 0.000588 AC: 9 AN: 15294

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68028

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.00238 Hom.: 6

Bravo AF: 0.00420

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	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	-0.35
CADD	Benign	8.2
DANN	Benign	0.73
PhyloP100		0.25
Mutation Taster		=96/4	polymorphism

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: rs111033476; hg19: chr11-76918426;