NM_000260.4:c.6028G>C

Variant names:

• chr11-77208780-G-C
• NM_000260.4:c.6028G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_000260.4(MYO7A):​c.6028G>C​(p.Asp2010His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000705 in 1,418,232 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D2010N) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: MYO7A NM_000260.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.60

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-77208780-G-A is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.906

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO7A	NM_000260.4	c.6028G>C	p.Asp2010His	missense_variant	Exon 44 of 49	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.6028G>C	p.Asp2010His	missense_variant	Exon 44 of 49	1	NM_000260.4	ENSP00000386331.3
MYO7A	ENST00000458637.6	c.5914G>C	p.Asp1972His	missense_variant	Exon 44 of 49	1		ENSP00000392185.2
MYO7A	ENST00000409619.6	c.5881G>C	p.Asp1961His	missense_variant	Exon 45 of 50	1		ENSP00000386635.2
MYO7A	ENST00000458169.2	c.3454G>C	p.Asp1152His	missense_variant	Exon 24 of 29	1		ENSP00000417017.2
MYO7A	ENST00000670577.1	n.*600G>C		non_coding_transcript_exon_variant	Exon 27 of 32			ENSP00000499323.1
MYO7A	ENST00000670577	n.*600G>C		3_prime_UTR_variant	Exon 27 of 30			ENSP00000499323.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.05e-7 AC: 1 AN: 1418232 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 701426

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: 9.18e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.83	D;.;.;D
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.91	D;D;D;D
MetaSVM	Uncertain	0.51	D
MutationAssessor	Pathogenic	3.5	H;.;.;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-6.8	D;D;D;D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.94
MutPred		0.68		Loss of helix (P = 0.1299);.;.;.;
MVP		0.93
MPC		0.47
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.99
gMVP		0.84

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-76919825;