rs727504551

Positions:

• chr1-215674103-T-C
• chr1-215674103-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM2 PM5 BP4_Moderate BP6_Moderate

The NM_206933.4(USH2A):​c.13808A>G​(p.His4603Arg) 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. 14/21 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. H4603P) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.08

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-215674103-T-G is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.15237898).
• BP6: Variant 1-215674103-T-C is Benign according to our data. Variant chr1-215674103-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 180059.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4	c.13808A>G	p.His4603Arg	missense_variant	63/72	ENST00000307340.8	NP_996816.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8	c.13808A>G	p.His4603Arg	missense_variant	63/72	1	NM_206933.4	ENSP00000305941	P1
USH2A	ENST00000674083.1	c.13808A>G	p.His4603Arg	missense_variant	63/73			ENSP00000501296

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 10, 2014

p.His4603Arg in exon 63 of USH2A: This variant is not expected to have clinical significance due to a lack of conservation across species, including mammals. Of note, the prairie vole, David's myotis, microbat and big brown bat have an argi nine (Arg) at this position despite moderate nearby amino acid conservation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	16
DANN	Benign	0.95
DEOGEN2	Benign	0.085	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.49	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	0.76	N;N
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.086
Sift	Benign	0.25	T
Sift4G	Uncertain	0.022	D
Polyphen		0.015	B
Vest4		0.14
MutPred		0.61		Gain of MoRF binding (P = 0.0627);
MVP		0.88
MPC		0.038
ClinPred		0.13	T
GERP RS		2.7
Varity_R		0.20
gMVP		0.53

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: rs727504551; hg19: chr1-215847445;