1-215675211-T-G

Position:

• chr1-215675211-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_206933.4(USH2A):​c.12700A>C​(p.Thr4234Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 3.87

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a domain Fibronectin type-III 27 (size 104) in uniprot entity USH2A_HUMAN there are 22 pathogenic changes around while only 7 benign (76%) in NM_206933.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.896
• PP5: Variant 1-215675211-T-G is Pathogenic according to our data. Variant chr1-215675211-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 228311.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4	c.12700A>C	p.Thr4234Pro	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.12700A>C	p.Thr4234Pro	missense_variant	63/72	1	NM_206933.4	ENSP00000305941	P1
USH2A	ENST00000674083.1	c.12700A>C	p.Thr4234Pro	missense_variant	63/73			ENSP00000501296

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Retinitis pigmentosa 39 Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	research	Ocular Genomics Institute, Massachusetts Eye and Ear	Apr 08, 2021	The USH2A c.12700A>C variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2. Based on this evidence we have classified this variant as Variant of Uncertain Significance. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 25, 2024	- -

Usher syndrome;C5680250:Rare genetic deafness Pathogenic:1

Likely pathogenic, flagged submission

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 07, 2015

The p.Thr4234Pro variant in USH2A has been reported as a homozygous variant in o ne individual with clinical features of Usher syndrome type 2 (Lenarduzzi 2015), and was absent from large race-matched population studies. Computational predic tion tools and conservation analyses of the predicted amino acid change at this position do not provide strong support for or against an impact to the protein. However, the nucleotide base affected by the variant (the adenosine (A) base at c.12700) is well conserved across species and splice prediction tools suggest th at the variant may impact splicing; though this data is not predictive enough to determine pathogenicity. In summary, although additional studies are required t o fully establish its clinical significance, this variant is likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.43	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.56	T
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Pathogenic	3.3	M
MutationTaster	Benign	0.98	D;D
PrimateAI	Benign	0.23	T
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.74
Sift	Benign	0.066	T
Sift4G	Uncertain	0.028	D
Polyphen		0.96	D
Vest4		0.42
MutPred		0.76		Gain of ubiquitination at K4239 (P = 0.2129);
MVP		0.96
MPC		0.25
ClinPred		0.98	D
GERP RS		4.1
Varity_R		0.88
gMVP		0.73

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: rs577938494; hg19: chr1-215848553; COSMIC: COSV56339858;