NM_000260.4:c.1721A>C

Variant names:

• chr11-77166086-A-C
• rs397516287
• NM_000260.4:c.1721A>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000260.4(MYO7A):​c.1721A>C​(p.His574Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000411 in 1,461,620 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: MYO7A NM_000260.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.52

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

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.839

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO7A	NM_000260.4	c.1721A>C	p.His574Pro	missense_variant	Exon 15 of 49	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.1721A>C	p.His574Pro	missense_variant	Exon 15 of 49	1	NM_000260.4	ENSP00000386331.3
MYO7A	ENST00000458637.6	c.1721A>C	p.His574Pro	missense_variant	Exon 15 of 49	1		ENSP00000392185.2
MYO7A	ENST00000409619.6	c.1688A>C	p.His563Pro	missense_variant	Exon 16 of 50	1		ENSP00000386635.2
MYO7A	ENST00000669443.1	c.29A>C	p.His10Pro	missense_variant	Exon 1 of 3			ENSP00000499530.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461620 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727082

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Dec 13, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The His574Pro variant in MYO7A has not been reported in the literature nor previ ously identified by our laboratory. Computational analyses (biochemical amino ac id properties, homology, PolyPhen2, SIFT, AlignGVGD) do not provide strong suppo rt for or against pathogenicity. In summary, the clinical significance of this v ariant cannot be determined with certainty at this time. -

Usher syndrome type 1;C1838701:Autosomal recessive nonsyndromic hearing loss 2 Uncertain:1

Apr 03, 2018

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.75	D;T;.;.
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.84	T;T;T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.84	D;D;D;D
MetaSVM	Uncertain	0.35	D
MutationAssessor	Benign	0.44	N;.;N;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-4.6	D;.;D;D
REVEL	Uncertain	0.63
Sift	Uncertain	0.023	D;.;D;D
Sift4G	Uncertain	0.057	T;D;T;T
Polyphen		0.48	P;.;.;.
Vest4		0.82
MutPred		0.56		Loss of helix (P = 0.079);Loss of helix (P = 0.079);Loss of helix (P = 0.079);.;
MVP		0.92
MPC		0.43
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.79
gMVP		0.78

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: rs397516287; hg19: chr11-76877132;