chr11-77182575-T-C

Variant names:

• chr11-77182575-T-C
• rs375050157
• NM_000260.4:c.3260T>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_000260.4(MYO7A):​c.3260T>C​(p.Leu1087Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as no classification for the single variant (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L1087R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 34)
• Consequence: MYO7A NM_000260.4 missense
• Clinical Significance: no classification for the single variant no classification for the single variant U:1
• Conservation: PhyloP100: 7.63

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a domain MyTH4 1 (size 236) in uniprot entity MYO7A_HUMAN there are 52 pathogenic changes around while only 13 benign (80%) in NM_000260.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.829

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO7A	NM_000260.4	c.3260T>C	p.Leu1087Pro	missense_variant	Exon 25 of 49	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.3260T>C	p.Leu1087Pro	missense_variant	Exon 25 of 49	1	NM_000260.4	ENSP00000386331.3
MYO7A	ENST00000458637.6	c.3260T>C	p.Leu1087Pro	missense_variant	Exon 25 of 49	1		ENSP00000392185.2
MYO7A	ENST00000409619.6	c.3227T>C	p.Leu1076Pro	missense_variant	Exon 26 of 50	1		ENSP00000386635.2
MYO7A	ENST00000458169.2	c.803T>C	p.Leu268Pro	missense_variant	Exon 5 of 29	1		ENSP00000417017.2
MYO7A	ENST00000670577.1	n.1100T>C		non_coding_transcript_exon_variant	Exon 8 of 32			ENSP00000499323.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 34

ClinVar

Significance: no classification for the single variant

Submissions summary: Uncertain:1

Revision: no classification for the single variant

Submissions by phenotype

Usher syndrome type 1 Uncertain:1

Jun 01, 2002

OMIM

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D;T;.;.;.;T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.83	D;D;D;D;D;D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Benign	2.0	M;.;M;.;.;.
PhyloP100		7.6
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.5	D;.;D;D;.;D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.012	D;.;D;D;.;D
Sift4G	Benign	0.13	T;T;T;T;.;T
Polyphen		0.99	D;.;.;.;.;.
Vest4		0.94
MutPred		0.48		Gain of ubiquitination at K1084 (P = 0.0645);Gain of ubiquitination at K1084 (P = 0.0645);Gain of ubiquitination at K1084 (P = 0.0645);.;.;.;
MVP		0.93
MPC		0.59
ClinPred		0.96	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.88
gMVP		0.72
Mutation Taster		=0/100	disease causing

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

Publications

LitVar

Other links and lift over

dbSNP: rs375050157; hg19: chr11-76893620;