rs36090425

Variant names:

• chr11-77177597-G-A
• rs36090425
• NM_000260.4:c.2236G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-77177597-G-A
• chr11-77177597-G-C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000260.4(MYO7A):​c.2236G>A​(p.Asp746Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00106 in 1,612,112 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D746A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0060 (13 hom., cov: 32)
  • Exomes 𝑓: 0.00054 (8 hom.)
• Consequence: MYO7A NM_000260.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 5.54
• Publications: 5 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 -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_000260.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.009173781).
• BP6: Variant 11-77177597-G-A is Benign according to our data. Variant chr11-77177597-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 43177.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00601 (915/152232) while in subpopulation AFR AF = 0.0209 (869/41536). AF 95% confidence interval is 0.0198. There are 13 homozygotes in GnomAd4. There are 433 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 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.2236G>A	p.Asp746Asn	missense	Exon 19 of 49	NP_000251.3	Q13402-1
	MYO7A	NM_001127180.2		c.2236G>A	p.Asp746Asn	missense	Exon 19 of 49	NP_001120652.1	Q13402-2
	MYO7A	NM_001369365.1		c.2203G>A	p.Asp735Asn	missense	Exon 20 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.2236G>A	p.Asp746Asn	missense	Exon 19 of 49	ENSP00000386331.3	Q13402-1
	MYO7A	ENST00000458637.6	TSL:1	c.2236G>A	p.Asp746Asn	missense	Exon 19 of 49	ENSP00000392185.2	Q13402-2
	MYO7A	ENST00000409619.6	TSL:1	c.2203G>A	p.Asp735Asn	missense	Exon 20 of 50	ENSP00000386635.2	Q13402-8

Frequencies

GnomAD3 genomes AF: 0.00600 AC: 912 AN: 152114 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.0209

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00148 AC: 363 AN: 245998 AF XY: 0.00104

Gnomad AFR exome AF: 0.0216

Gnomad AMR exome AF: 0.000787

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000449

Gnomad OTH exome AF: 0.00101

GnomAD4 exome AF: 0.000543 AC: 792 AN: 1459880 Hom.: 8 Cov.: 31 AF XY: 0.000457 AC XY: 332 AN XY: 725994

African (AFR) AF: 0.0189 AC: 633 AN: 33462

American (AMR) AF: 0.000762 AC: 34 AN: 44614

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.0000233 AC: 2 AN: 85720

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52832

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5766

European-Non Finnish (NFE) AF: 0.0000288 AC: 32 AN: 1111384

Other (OTH) AF: 0.00131 AC: 79 AN: 60330

GnomAD4 genome AF: 0.00601 AC: 915 AN: 152232 Hom.: 13 Cov.: 32 AF XY: 0.00582 AC XY: 433 AN XY: 74434

African (AFR) AF: 0.0209 AC: 869 AN: 41536

American (AMR) AF: 0.00203 AC: 31 AN: 15284

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5170

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68010

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.0198 Hom.: 2356

Bravo AF: 0.00666

ESP6500AA AF: 0.0174 AC: 74

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00191 AC: 231

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	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
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.49
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0092	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.4	L
PhyloP100		5.5
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.15
Sift	Benign	0.31	T
Sift4G	Benign	0.32	T
Polyphen		0.95	P
Vest4		0.59
MVP		0.84
MPC		0.086
ClinPred		0.017	T
GERP RS		5.0
Varity_R		0.29
gMVP		0.62
Mutation Taster		=48/52	disease causing

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: rs36090425; hg19: chr11-76888643; COSMIC: COSV68685280; COSMIC: COSV68685280;