rs111033498

Variant names:

• chr1-215640566-G-A
• rs111033498
• NM_206933.4:c.14960C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-215640566-G-A
• chr1-215640566-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_206933.4(USH2A):​c.14960C>T​(p.Ala4987Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00219 in 1,613,720 control chromosomes in the GnomAD database, including 116 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A4987A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0062 (29 hom., cov: 31)
  • Exomes 𝑓: 0.0018 (87 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 2.90
• Publications: 6 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026477277).
• BP6: Variant 1-215640566-G-A is Benign according to our data. Variant chr1-215640566-G-A is described in ClinVar as Benign. ClinVar VariationId is 48451.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0513 is higher than 0.05.

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.14960C>T	p.Ala4987Val	missense	Exon 68 of 72	NP_996816.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH2A	ENST00000307340.8	TSL:1 MANE Select	c.14960C>T	p.Ala4987Val	missense	Exon 68 of 72	ENSP00000305941.3
	USH2A	ENST00000674083.1		c.14960C>T	p.Ala4987Val	missense	Exon 68 of 73	ENSP00000501296.1

Frequencies

GnomAD3 genomes AF: 0.00614 AC: 933 AN: 151838 Hom.: 29 Cov.: 31

Gnomad AFR AF: 0.00179

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0539

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.0130

GnomAD2 exomes AF: 0.00690 AC: 1723 AN: 249782 AF XY: 0.00523

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.0474

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000196

Gnomad OTH exome AF: 0.00637

GnomAD4 exome AF: 0.00177 AC: 2586 AN: 1461764 Hom.: 87 Cov.: 32 AF XY: 0.00149 AC XY: 1085 AN XY: 727192

African (AFR) AF: 0.00152 AC: 51 AN: 33476

American (AMR) AF: 0.0514 AC: 2298 AN: 44720

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

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39694

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86250

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5686

European-Non Finnish (NFE) AF: 0.0000594 AC: 66 AN: 1111998

Other (OTH) AF: 0.00262 AC: 158 AN: 60388

GnomAD4 genome AF: 0.00620 AC: 942 AN: 151956 Hom.: 29 Cov.: 31 AF XY: 0.00703 AC XY: 522 AN XY: 74256

African (AFR) AF: 0.00181 AC: 75 AN: 41468

American (AMR) AF: 0.0543 AC: 829 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4758

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10578

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

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 67960

Other (OTH) AF: 0.0128 AC: 27 AN: 2104

Alfa AF: 0.00108 Hom.: 7

Bravo AF: 0.00866

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00468 AC: 568

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	1	Retinal dystrophy (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	0.087
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	14
DANN	Benign	0.93
DEOGEN2	Benign	0.047	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.67
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.68	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.76	N
PhyloP100		2.9
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.13
Sift	Benign	0.43	T
Sift4G	Benign	0.28	T
Polyphen		0.0060	B
Vest4		0.14
MVP		0.73
MPC		0.030
ClinPred		0.0065	T
GERP RS		0.60
Varity_R		0.023
gMVP		0.20
Mutation Taster		=90/10	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs111033498; hg19: chr1-215813908; COSMIC: COSV56353125;