rs727504307

Variant names:

• chr1-215779956-C-A
• rs727504307
• NM_206933.4:c.10826G>T

Your query was ambiguous. Multiple possible variants found:

• chr1-215779956-C-A
• chr1-215779956-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM1 BP4

The NM_206933.4(USH2A):​c.10826G>T​(p.Ser3609Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,461,884 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S3609T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000019 (1 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:1
• Conservation: PhyloP100: 1.92
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_206933.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.35757384).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_206933.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH2A	NM_206933.4	MANE Select	c.10826G>T	p.Ser3609Ile	missense	Exon 55 of 72	NP_996816.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH2A	ENST00000307340.8	TSL:1 MANE Select	c.10826G>T	p.Ser3609Ile	missense	Exon 55 of 72	ENSP00000305941.3
	USH2A	ENST00000674083.1		c.10826G>T	p.Ser3609Ile	missense	Exon 55 of 73	ENSP00000501296.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000915 AC: 23 AN: 251356 AF XY: 0.0000883

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000665

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000192 AC: 28 AN: 1461884 Hom.: 1 Cov.: 32 AF XY: 0.0000193 AC XY: 14 AN XY: 727242

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.000626 AC: 28 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.0000494 AC: 6

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	1	not provided (4)
-	1	-	Inborn genetic diseases (1)
-	1	-	not specified (1)
-	1	-	Usher syndrome type 2A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.24	T
Eigen	Benign	0.0052
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.66	T
M_CAP	Pathogenic	0.34	D
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		1.9
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.23
Sift	Benign	0.098	T
Sift4G	Uncertain	0.056	T
Polyphen		0.0080	B
Vest4		0.31
MutPred		0.64		Loss of disorder (P = 0.0536)
MVP		0.93
MPC		0.047
ClinPred		0.16	T
GERP RS		3.8
Varity_R		0.28
gMVP		0.71
Mutation Taster		=84/16	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: rs727504307; hg19: chr1-215953298;