rs201190539

Variant names:

• chr1-216198326-G-A
• rs201190539
• NM_206933.4:c.4070C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-216198326-G-A
• chr1-216198326-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_206933.4(USH2A):​c.4070C>T​(p.Thr1357Met) variant causes a missense change. The variant allele was found at a frequency of 0.000126 in 1,613,810 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. T1357T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (1 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 6.37
• Publications: 5 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-AS1 (HGNC:40606): (USH2A antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH2A	NM_206933.4	MANE Select	c.4070C>T	p.Thr1357Met	missense	Exon 18 of 72	NP_996816.3	O75445-1
	USH2A	NM_007123.6		c.4070C>T	p.Thr1357Met	missense	Exon 18 of 21	NP_009054.6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH2A	ENST00000307340.8	TSL:1 MANE Select	c.4070C>T	p.Thr1357Met	missense	Exon 18 of 72	ENSP00000305941.3	O75445-1
	USH2A	ENST00000366942.3	TSL:1	c.4070C>T	p.Thr1357Met	missense	Exon 18 of 21	ENSP00000355909.3	O75445-2
	USH2A	ENST00000674083.1		c.4070C>T	p.Thr1357Met	missense	Exon 18 of 73	ENSP00000501296.1	O75445-3

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152016 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000773

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000167 AC: 42 AN: 250890 AF XY: 0.000199

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000927

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000134 AC: 196 AN: 1461680 Hom.: 1 Cov.: 31 AF XY: 0.000160 AC XY: 116 AN XY: 727146

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00287 AC: 114 AN: 39654

South Asian (SAS) AF: 0.000765 AC: 66 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5766

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111916

Other (OTH) AF: 0.000116 AC: 7 AN: 60390

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152130 Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7 AN XY: 74326

African (AFR) AF: 0.00 AC: 0 AN: 41516

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000775 AC: 4 AN: 5160

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10554

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.0000261 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.000181 AC: 22

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 (2)
-	1	-	not provided (1)
-	1	-	Retinal dystrophy (1)
-	1	-	Retinitis pigmentosa (1)
-	1	-	Retinitis pigmentosa 39 (1)
-	1	-	Usher syndrome type 2A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.090	T
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Uncertain	0.64	D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Pathogenic	4.4	H
PhyloP100		6.4
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-4.2	D
REVEL	Uncertain	0.50
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.78
MVP		0.98
MPC		0.23
ClinPred		0.74	D
GERP RS		4.7
Varity_R		0.41
gMVP		0.74
Mutation Taster		=2/98	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs201190539; hg19: chr1-216371668; COSMIC: COSV56407503; COSMIC: COSV56407503;