rs727503728

chr1-216083500-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_206933.4(USH2A):c.5254T>G(p.Leu1752Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L1752W) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.29

Genes affected

USH2A (HGNC:12601): (usherin) This gene encodes a protein that contains laminin EGF motifs, a pentaxin domain, and many fibronectin type III motifs. The protein is found in the basement membrane, and may be important in development and homeostasis of the inner ear and retina. Mutations within this gene have been associated with Usher syndrome type IIa and retinitis pigmentosa. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]

USH2A-AS2 (HGNC:40605): (USH2A antisense RNA 2)

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a domain Laminin G-like 2 (size 177) in uniprot entity USH2A_HUMAN there are 75 pathogenic changes around while only 8 benign (90%) in NM_206933.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4	c.5254T>G	p.Leu1752Val	missense_variant	26/72	ENST00000307340.8
USH2A-AS2	NR_125992.1	n.266-3222A>C		intron_variant, non_coding_transcript_variant
USH2A-AS2	NR_125993.1	n.137-3222A>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8	c.5254T>G	p.Leu1752Val	missense_variant	26/72	1	NM_206933.4	P1
USH2A-AS2	ENST00000446411.5	n.266-3222A>C		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 02, 2014

The p.Leu1752Val variant in USH2A has not been previously reported in individual s with hearing loss or in large population studies. Computational prediction too ls and conservation analysis do not provide strong support for or against an imp act to the protein. In summary, the clinical significance of the p.Leu1752Val va riant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.017	T
BayesDel_noAF	Benign	-0.26
Cadd	Benign	18
Dann	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.41	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	0.99	D;D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.62
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.010	D
Polyphen		0.98	D
Vest4		0.52
MutPred		0.60		Loss of stability (P = 0.0371);
MVP		0.85
MPC		0.23
ClinPred		0.89	D
GERP RS		3.3
Varity_R		0.26
gMVP		0.27

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: rs727503728; hg19: chr1-216256842;