NM_000260.4:c.4845C>A

Variant names:

• chr11-77199811-C-A
• rs61900036
• NM_000260.4:c.4845C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_000260.4(MYO7A):​c.4845C>A​(p.Pro1615Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00164 in 1,588,208 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (4 hom.)
• Consequence: MYO7A NM_000260.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:7
• Conservation: PhyloP100: 0.246
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 11-77199811-C-A is Benign according to our data. Variant chr11-77199811-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 178625.
• BP7: Synonymous conserved (PhyloP=0.246 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00116 (176/152208) while in subpopulation NFE AF = 0.00187 (127/68042). AF 95% confidence interval is 0.0016. There are 0 homozygotes in GnomAd4. There are 79 alleles in the male GnomAd4 subpopulation. Median coverage is 32. 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO7A	NM_000260.4	MANE Select	c.4845C>A	p.Pro1615Pro	synonymous	Exon 35 of 49	NP_000251.3
	MYO7A	NM_001127180.2		c.4731C>A	p.Pro1577Pro	synonymous	Exon 35 of 49	NP_001120652.1
	MYO7A	NM_001369365.1		c.4698C>A	p.Pro1566Pro	synonymous	Exon 36 of 50	NP_001356294.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO7A	ENST00000409709.9	TSL:1 MANE Select	c.4845C>A	p.Pro1615Pro	synonymous	Exon 35 of 49	ENSP00000386331.3
	MYO7A	ENST00000458637.6	TSL:1	c.4731C>A	p.Pro1577Pro	synonymous	Exon 35 of 49	ENSP00000392185.2
	MYO7A	ENST00000409619.6	TSL:1	c.4698C>A	p.Pro1566Pro	synonymous	Exon 36 of 50	ENSP00000386635.2

Frequencies

GnomAD3 genomes AF: 0.00116 AC: 176 AN: 152208 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00187

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00124 AC: 294 AN: 236764 AF XY: 0.00128

Gnomad AFR exome AF: 0.000196

Gnomad AMR exome AF: 0.000297

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00392

Gnomad NFE exome AF: 0.00179

Gnomad OTH exome AF: 0.00175

GnomAD4 exome AF: 0.00169 AC: 2431 AN: 1436000 Hom.: 4 Cov.: 33 AF XY: 0.00167 AC XY: 1182 AN XY: 709692

African (AFR) AF: 0.000392 AC: 13 AN: 33124

American (AMR) AF: 0.000274 AC: 12 AN: 43824

Ashkenazi Jewish (ASJ) AF: 0.0000399 AC: 1 AN: 25070

East Asian (EAS) AF: 0.00 AC: 0 AN: 39130

South Asian (SAS) AF: 0.0000119 AC: 1 AN: 83940

European-Finnish (FIN) AF: 0.00341 AC: 179 AN: 52468

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5676

European-Non Finnish (NFE) AF: 0.00197 AC: 2157 AN: 1093588

Other (OTH) AF: 0.00115 AC: 68 AN: 59180

GnomAD4 genome AF: 0.00116 AC: 176 AN: 152208 Hom.: 0 Cov.: 32 AF XY: 0.00106 AC XY: 79 AN XY: 74364

African (AFR) AF: 0.000290 AC: 12 AN: 41442

American (AMR) AF: 0.000196 AC: 3 AN: 15288

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00282 AC: 30 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00187 AC: 127 AN: 68042

Other (OTH) AF: 0.00191 AC: 4 AN: 2092

Alfa AF: 0.00148 Hom.: 1

Bravo AF: 0.000835

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	7.0
DANN	Benign	0.75
PhyloP100		0.25
Mutation Taster		=100/0	polymorphism

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: rs61900036; hg19: chr11-76910856;