NM_000260.4:c.2181T>C

Variant names:

• chr11-77175458-T-C
• rs373656667
• NM_000260.4:c.2181T>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_000260.4(MYO7A):​c.2181T>C​(p.Phe727Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000252 in 1,613,202 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00025 (1 hom.)
• Consequence: MYO7A NM_000260.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: -0.507
• Publications: 0 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 11-77175458-T-C is Benign according to our data. Variant chr11-77175458-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 227679.
• BP7: Synonymous conserved (PhyloP=-0.507 with no splicing effect.

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.2181T>C	p.Phe727Phe	synonymous	Exon 18 of 49	NP_000251.3	Q13402-1
	MYO7A	NM_001127180.2		c.2181T>C	p.Phe727Phe	synonymous	Exon 18 of 49	NP_001120652.1	Q13402-2
	MYO7A	NM_001369365.1		c.2148T>C	p.Phe716Phe	synonymous	Exon 19 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.2181T>C	p.Phe727Phe	synonymous	Exon 18 of 49	ENSP00000386331.3	Q13402-1
	MYO7A	ENST00000458637.6	TSL:1	c.2181T>C	p.Phe727Phe	synonymous	Exon 18 of 49	ENSP00000392185.2	Q13402-2
	MYO7A	ENST00000409619.6	TSL:1	c.2148T>C	p.Phe716Phe	synonymous	Exon 19 of 50	ENSP00000386635.2	Q13402-8

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 45 AN: 152196 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000362 AC: 90 AN: 248900 AF XY: 0.000377

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00398

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000346

Gnomad OTH exome AF: 0.000992

GnomAD4 exome AF: 0.000248 AC: 362 AN: 1460888 Hom.: 1 Cov.: 31 AF XY: 0.000275 AC XY: 200 AN XY: 726744

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00478 AC: 125 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.0000190 AC: 1 AN: 52614

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.000183 AC: 203 AN: 1111840

Other (OTH) AF: 0.000431 AC: 26 AN: 60370

GnomAD4 genome AF: 0.000295 AC: 45 AN: 152314 Hom.: 0 Cov.: 33 AF XY: 0.000269 AC XY: 20 AN XY: 74480

African (AFR) AF: 0.000120 AC: 5 AN: 41568

American (AMR) AF: 0.0000653 AC: 1 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00605 AC: 21 AN: 3470

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

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: 0.000265 AC: 18 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000787 Hom.: 0

Bravo AF: 0.000340

EpiCase AF: 0.000382

EpiControl AF: 0.000711

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	7.4
DANN	Benign	0.64
PhyloP100		-0.51
Mutation Taster		=94/6	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: rs373656667; hg19: chr11-76886504;