rs876657532

Variant names:

• chr11-77147964-C-G
• rs876657532
• NM_000260.4:c.285+14C>G

Your query was ambiguous. Multiple possible variants found:

• chr11-77147964-C-G
• chr11-77147964-C-T

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-4 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -4 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_StrongBP6_Moderate

The NM_000260.4(MYO7A):c.285+14C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00000196 (AC=3) in the gnomAD database across 1,531,464 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.00000801. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: MYO7A NM_000260.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.329
• 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):

• autosomal dominant nonsyndromic hearing loss 11

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Natera, Labcorp Genetics (formerly Invitae), Ambry Genetics
• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, PanelApp Australia
• autosomal recessive nonsyndromic hearing loss 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• Usher syndrome type 1

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

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, 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

Classification according to ACMG Germline Pathogenicity v2019

Specifications for MYO7A are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Likely_benign. The variant received -4 points.

• PM2: Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.00000801 — very rare for AD+AR gene (base 0.0001, raised to 0.000405 by highest known P/LP ClinVar AF 0.000405) — PM2 moderate.
• BP4: Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
• BP6: ClinVar 1-star benign — moderate (BP6); ClinVar germline classification: Benign/Likely Benign, 1 star(s).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000260.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO7A	NM_000260.4	MANE Select	c.285+14C>G		intron	N/A	NP_000251.3	Q13402-1
	MYO7A	NM_001127180.2		c.285+14C>G		intron	N/A	NP_001120652.1	Q13402-2
	MYO7A	NM_001369365.1		c.252+14C>G		intron	N/A	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.285+14C>G		intron	N/A	ENSP00000386331.3	Q13402-1
	MYO7A	ENST00000458637.6	TSL:1	c.285+14C>G		intron	N/A	ENSP00000392185.2	Q13402-2
	MYO7A	ENST00000409619.6	TSL:1	c.252+14C>G		intron	N/A	ENSP00000386635.2	Q13402-8

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 5 sources Large-scale international reference populations
GnomAD3 genomes	0.0000132	2	0	152070	32
GnomAD4 exome	7.25e-7	1	0	1379394	34
GnomAD4 genome	0.0000132	2	0	152070	32
TOPMed (Bravo)	0.00000378
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	0.00	0	0	16840

Showing 5 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
BipEx(Bipolar disorder (including schizoaffective))	0.0000354	1	28228	0.00	0	28678

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational Scores

Algorithm	Calibrated prediction	Prediction	Score
AlphaGenome AVI	Benign	-	4.6
BayesDel_noAF	Benign	-	-0.80
CADD	Benign	-	0.91
DANN	Benign	-	0.31
GPN-Star LLR	N/A	-	0.13
GPN-Star score	N/A	-	-0.13
PhyloP100	Benign	-	0.33

Showing 7 of 7 scores

Splicing Scores

Algorithm	Calibrated prediction	Prediction	Score
Pangolin (max)	Benign	-	0.0
SpliceAI score (max)	Benign	- Details are displayed if max score is > 0.2	0.0

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs876657532;

hg19: chr11-76859010;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar