rs397518001

Variant names:

• chr1-215628832-C-T
• rs397518001
• NM_206933.4:c.15501G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_206933.4(USH2A):​c.15501G>A​(p.Met5167Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M5167V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.22
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• Usher syndrome type 2

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Usher syndrome type 2A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• retinitis pigmentosa 39

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16944325).
• BP6: Variant 1-215628832-C-T is Benign according to our data. Variant chr1-215628832-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 48466.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH2A	NM_206933.4	c.15501G>A	p.Met5167Ile	missense_variant	Exon 71 of 72	ENST00000307340.8	NP_996816.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8	c.15501G>A	p.Met5167Ile	missense_variant	Exon 71 of 72	1	NM_206933.4	ENSP00000305941.3
USH2A	ENST00000674083.1	c.15573G>A	p.Met5191Ile	missense_variant	Exon 72 of 73			ENSP00000501296.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Aug 02, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Met5167Ile in exon 71 of USH2A: This variant is not expected to have clinical si gnificance because computational analyses (PolyPhen2, SIFT, AlignGVGD) do not su ggest a high likelihood of clinical significance primarily based upon lack of co nservation across species. Of note, chicken has an isoleucine at this position. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	18
DANN	Benign	0.93
DEOGEN2	Benign	0.044	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.037
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
PhyloP100		1.2
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.57	N
REVEL	Benign	0.042
Sift	Benign	0.36	T
Sift4G	Benign	0.62	T
Polyphen		0.0050	B
Vest4		0.46
MutPred		0.28		Gain of catalytic residue at S5171 (P = 0.3431);
MVP		0.48
MPC		0.032
ClinPred		0.38	T
GERP RS		4.7
Varity_R		0.22
gMVP		0.074
Mutation Taster		=81/19	polymorphism

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

Other links and lift over

dbSNP: rs397518001; hg19: chr1-215802174;