rs4129843

Variant names:

• chr1-215813880-T-C
• rs4129843
• NM_206933.4:c.9595A>G

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.9595A>G​(p.Asn3199Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0513 in 1,613,676 control chromosomes in the GnomAD database, including 2,777 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. N3199N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.056 (301 hom., cov: 32)
  • Exomes 𝑓: 0.051 (2476 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.195
• Publications: 30 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=0.0016355515).
• BP6: Variant 1-215813880-T-C is Benign according to our data. Variant chr1-215813880-T-C is described in ClinVar as Benign. ClinVar VariationId is 48631.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.143 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH2A	NM_206933.4	MANE Select	c.9595A>G	p.Asn3199Asp	missense	Exon 49 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.9595A>G	p.Asn3199Asp	missense	Exon 49 of 72	ENSP00000305941.3
	USH2A	ENST00000674083.1		c.9595A>G	p.Asn3199Asp	missense	Exon 49 of 73	ENSP00000501296.1

Frequencies

GnomAD3 genomes AF: 0.0556 AC: 8462 AN: 152058 Hom.: 299 Cov.: 32

Gnomad AFR AF: 0.0785

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.0619

Gnomad ASJ AF: 0.00864

Gnomad EAS AF: 0.152

Gnomad SAS AF: 0.0767

Gnomad FIN AF: 0.00651

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0421

Gnomad OTH AF: 0.0560

GnomAD2 exomes AF: 0.0549 AC: 13784 AN: 250962 AF XY: 0.0540

Gnomad AFR exome AF: 0.0814

Gnomad AMR exome AF: 0.0613

Gnomad ASJ exome AF: 0.00805

Gnomad EAS exome AF: 0.169

Gnomad FIN exome AF: 0.00795

Gnomad NFE exome AF: 0.0373

Gnomad OTH exome AF: 0.0438

GnomAD4 exome AF: 0.0509 AC: 74362 AN: 1461500 Hom.: 2476 Cov.: 31 AF XY: 0.0511 AC XY: 37145 AN XY: 727048

African (AFR) AF: 0.0747 AC: 2501 AN: 33460

American (AMR) AF: 0.0617 AC: 2761 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00831 AC: 217 AN: 26114

East Asian (EAS) AF: 0.151 AC: 5982 AN: 39678

South Asian (SAS) AF: 0.0806 AC: 6950 AN: 86256

European-Finnish (FIN) AF: 0.00932 AC: 498 AN: 53408

Middle Eastern (MID) AF: 0.0359 AC: 207 AN: 5764

European-Non Finnish (NFE) AF: 0.0464 AC: 51607 AN: 1111720

Other (OTH) AF: 0.0603 AC: 3639 AN: 60378

GnomAD4 genome AF: 0.0557 AC: 8477 AN: 152176 Hom.: 301 Cov.: 32 AF XY: 0.0553 AC XY: 4117 AN XY: 74398

African (AFR) AF: 0.0787 AC: 3268 AN: 41514

American (AMR) AF: 0.0617 AC: 942 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00864 AC: 30 AN: 3472

East Asian (EAS) AF: 0.151 AC: 785 AN: 5182

South Asian (SAS) AF: 0.0765 AC: 369 AN: 4822

European-Finnish (FIN) AF: 0.00651 AC: 69 AN: 10604

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0421 AC: 2862 AN: 68004

Other (OTH) AF: 0.0578 AC: 122 AN: 2110

Alfa AF: 0.0473 Hom.: 741

Bravo AF: 0.0599

TwinsUK AF: 0.0499 AC: 185

ALSPAC AF: 0.0420 AC: 162

ESP6500AA AF: 0.0781 AC: 344

ESP6500EA AF: 0.0398 AC: 342

ExAC AF: 0.0551 AC: 6690

Asia WGS AF: 0.127 AC: 440 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	2	Usher syndrome type 2A (2)
-	-	1	Retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.87	T
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.8
DANN	Benign	0.19
DEOGEN2	Benign	0.035	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.51	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-1.8	N
PhyloP100		0.20
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.17	N
REVEL	Benign	0.042
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.015
MPC		0.032
ClinPred		0.0043	T
GERP RS		-0.53
Varity_R		0.042
gMVP		0.13
Mutation Taster		=92/8	polymorphism (auto)

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: rs4129843; hg19: chr1-215987222; COSMIC: COSV56343447;