NM_000260.4:c.285+14C>T

Variant names:

• chr11-77147964-C-T
• rs876657532
• NM_000260.4:c.285+14C>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>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00000145 (AC=2) in the gnomAD database across 1,379,394 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.00000031. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (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.

Classification was made for transcript:

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

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.00000031 — very rare for AD+AR gene (base 0.0001, raised to 0.000405 by highest known P/LP ClinVar AF 0.000405) — PM2 moderate.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
	BP6Reputable source reports benign		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>T	intron	Intron 4 of 48	Prot: NP_000251.3 UniProt:
	MYO7A NM_001127180.2		c.285+14C>T	intron	Intron 4 of 48	Prot: NP_001120652.1 UniProt:
	MYO7A NM_001369365.1		c.252+14C>T	intron	Intron 5 of 49	Prot: NP_001356294.1 UniProt:

MYO7A NM_000260.4

MANE Select

HGVSc / HGVSpc.285+14C>T

Exon rankIntron 4 of 48

intron

Prot: NP_000251.3UniProt: Q13402-1

MYO7A NM_001127180.2

HGVSc / HGVSpc.285+14C>T

Exon rankIntron 4 of 48

intron

Prot: NP_001120652.1UniProt: Q13402-2

MYO7A NM_001369365.1

HGVSc / HGVSpc.252+14C>T

Exon rankIntron 5 of 49

intron

Prot: NP_001356294.1UniProt: Q13402-8

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	MYO7A ENST00000409709.9	TSL:1MANE Select	c.285+14C>T	intron	Intron 4 of 48	Prot: ENSP00000386331.3 UniProt:
	MYO7A ENST00000458637.6	TSL:1	c.285+14C>T	intron	Intron 4 of 48	Prot: ENSP00000392185.2 UniProt:
	MYO7A ENST00000409619.6	TSL:1	c.252+14C>T	intron	Intron 5 of 49	Prot: ENSP00000386635.2 UniProt:

MYO7A ENST00000409709.9

TSL:1MANE Select

HGVSc / HGVSpc.285+14C>T

Exon rankIntron 4 of 48

intron

Prot: ENSP00000386331.3UniProt: Q13402-1

MYO7A ENST00000458637.6

TSL:1

HGVSc / HGVSpc.285+14C>T

Exon rankIntron 4 of 48

intron

Prot: ENSP00000392185.2UniProt: Q13402-2

MYO7A ENST00000409619.6

TSL:1

HGVSc / HGVSpc.252+14C>T

Exon rankIntron 5 of 49

intron

Prot: ENSP00000386635.2UniProt: 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	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF: 0.00000145	AC:2	Hom:0	AN:1379394	Cov:34
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32
TOPMed (Bravo)	AF: 0.00000378	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:16840	Cov:

Showing 5 sources

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	5.5
BayesDel_noAF	Benign	-0.78
CADD	Benign	2.7
DANN	Benign	0.94
GPN-Star LLR	N/A	-0.59
GPN-Star score	N/A	0.59
PhyloP100	Benign	0.33

Showing 7 of 7 scores

Splicing Scores

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

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.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs876657532;

hg19: chr11-76859010;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar