rs727503735

Positions:

• chr1-216217405-G-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_206933.4(USH2A):​c.3139C>G​(p.Leu1047Val) variant causes a missense change. The variant allele was found at a frequency of 0.000098 in 1,612,940 control chromosomes in the GnomAD database, including 1 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L1047L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000099 (1 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 4.37

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

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.018493354).
• BP6: Variant 1-216217405-G-C is Benign according to our data. Variant chr1-216217405-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 166512.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=1, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4	c.3139C>G	p.Leu1047Val	missense_variant	15/72	ENST00000307340.8	NP_996816.3
USH2A	NM_007123.6	c.3139C>G	p.Leu1047Val	missense_variant	15/21		NP_009054.6
USH2A-AS1	XR_922596.4	n.692-7982G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8	c.3139C>G	p.Leu1047Val	missense_variant	15/72	1	NM_206933.4	ENSP00000305941.3
USH2A	ENST00000366942.3	c.3139C>G	p.Leu1047Val	missense_variant	15/21	1		ENSP00000355909.3
USH2A	ENST00000674083.1	c.3139C>G	p.Leu1047Val	missense_variant	15/73			ENSP00000501296.1

Frequencies

GnomAD3 genomes AF: 0.0000921 AC: 14 AN: 152060 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000216 AC: 54 AN: 250414 Hom.: 0 AF XY: 0.000200 AC XY: 27 AN XY: 135324

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00378

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000531

Gnomad OTH exome AF: 0.000983

GnomAD4 exome AF: 0.0000986 AC: 144 AN: 1460880 Hom.: 1 Cov.: 33 AF XY: 0.0000949 AC XY: 69 AN XY: 726746

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00398

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.000265

GnomAD4 genome AF: 0.0000921 AC: 14 AN: 152060 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74276

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000405 Hom.: 0

Bravo AF: 0.0000982

ExAC AF: 0.0000989 AC: 12

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 17, 2013

Variant classified as Uncertain Significance - Favor Benign. The Leu1047Val vari ant in USH2A has been reported in 2 individuals with autosomal recessive retinit is pigmentosa, however it was not reported whether these individuals had a secon d variant in the USH2A gene (Jiad-Seyed-Ahmadi, 2003). This variant was not iden tified in large population. Computational analysis (biochemical amino acid prope rties, AlignGVGD, PolyPhen2, and SIFT) suggest the variant may not impact the pr otein, and the Leu1047 residue is not conserved across species with rock hyrax having a valine (Val) at that position. However, this data is not sufficient to rule out a pathogenic role. In summary, the clinical significance of this varian t cannot be determined; however based upon the lack of conservation and the comp utational data, we would lean toward a likely benign role. -

Usher syndrome type 2A Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Retinitis pigmentosa Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Sep 15, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.036	T;.
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.093
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.71	T;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.018	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L;L
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.33	N;N
REVEL	Benign	0.089
Sift	Benign	0.29	T;T
Sift4G	Benign	0.29	T;T
Polyphen		0.55	P;B
Vest4		0.26
MutPred		0.43		Gain of disorder (P = 0.2296);Gain of disorder (P = 0.2296);
MVP		0.83
MPC		0.078
ClinPred		0.084	T
GERP RS		3.3
Varity_R		0.076
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs727503735; hg19: chr1-216390747;