rs111033333

Variant names:

• chr1-216097127-G-A
• rs111033333
• NM_206933.4:c.4714C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-216097127-G-A
• chr1-216097127-G-C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BS1_Supporting BP2

This summary comes from the ClinGen Evidence Repository: The p.Leu1572Phe variant in USH2A gene has a filtering allele frequency= 0.12% in Latino in gnomAD (54/35388 with 95% CI) which is a higher frequency than would be expected for an autosomal recessive pathogenic variant based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (BS1 supporting). It was reported in multiple publications as a polymorphism or as non-pathogenic based on detection among normal control chromosomes or other evidence (PMID:18273898, 19881469 and 17085681). Although the variant was reported in trans with c.2299delG in one patient diagnosed with Usher syndrome type II and in another with unclassified Usher syndrome (PMID:25097241 and 28944237), it was also identified in cis with c.2299delG; p.Glu767Serfs and in unknown configuration with c.2299delG and a stop codon (PMID:25472526), both in patients with Usher syndrome type II (BP2; PMID:20507924, 25097241, 17405132 and 26969326). Computational prediction using REVEL was 0.65 which did not meet the Hearing Loss Expert Panel (HL EP) specified threshold of >0.7 for PP3. In summary, this variant meets criteria to be classified as likely benign for autosomal recessive Usher syndrome, type 2A based on the HL EP-specified ACMG/AMP criteria applied (BS1, BP2). LINK:https://erepo.genome.network/evrepo/ui/classification/CA143497/MONDO:0019501/005

• Frequency:
  • Genomes: 𝑓 0.00059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (2 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Likely benign reviewed by expert panel U:1 B:10 O:1
• Conservation: PhyloP100: 2.40
• Publications: 28 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 2A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• Usher syndrome type 2

  Inheritance: Unknown, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• retinitis pigmentosa 39

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Specifications for USH2A are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP2: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: For more information check the summary or visit ClinGen Evidence Repository.

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.4714C>T	p.Leu1572Phe	missense	Exon 22 of 72	NP_996816.3	O75445-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH2A	ENST00000307340.8	TSL:1 MANE Select	c.4714C>T	p.Leu1572Phe	missense	Exon 22 of 72	ENSP00000305941.3	O75445-1
	USH2A	ENST00000674083.1		c.4714C>T	p.Leu1572Phe	missense	Exon 22 of 73	ENSP00000501296.1	O75445-3

Frequencies

GnomAD3 genomes AF: 0.000591 AC: 90 AN: 152192 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00107

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000776 AC: 195 AN: 251270 AF XY: 0.000766

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00153

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00111

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00112 AC: 1643 AN: 1461800 Hom.: 2 Cov.: 31 AF XY: 0.00108 AC XY: 788 AN XY: 727194

African (AFR) AF: 0.000299 AC: 10 AN: 33476

American (AMR) AF: 0.00150 AC: 67 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

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

European-Non Finnish (NFE) AF: 0.00137 AC: 1524 AN: 1111970

Other (OTH) AF: 0.000679 AC: 41 AN: 60390

GnomAD4 genome AF: 0.000591 AC: 90 AN: 152310 Hom.: 0 Cov.: 33 AF XY: 0.000510 AC XY: 38 AN XY: 74476

African (AFR) AF: 0.000144 AC: 6 AN: 41576

American (AMR) AF: 0.000654 AC: 10 AN: 15298

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.00107 AC: 73 AN: 68024

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.00102 Hom.: 1

Bravo AF: 0.000771

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.000782 AC: 95

EpiCase AF: 0.00136

EpiControl AF: 0.000652

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (5)
-	-	4	not specified (4)
-	1	-	Inborn genetic diseases (1)
-	-	1	Retinitis pigmentosa (1)
-	-	1	Usher syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.81	T
M_CAP	Pathogenic	0.35	D
MetaRNN	Benign	0.12	T
MetaSVM	Uncertain	0.63	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		2.4
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-2.4	N
REVEL	Pathogenic	0.66
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.98	D
Vest4		0.55
MVP		0.89
MPC		0.23
ClinPred		0.074	T
GERP RS		4.0
Varity_R		0.38
gMVP		0.52
Mutation Taster		=8/92	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs111033333; hg19: chr1-216270469;