rs139474806

chr1-215674572-T-Achr1-215674572-T-C

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 14P and 1B. PM1 PM2 PM5 PP5_Very_Strong BP4

The NM_206933.4(USH2A):c.13339A>T(p.Met4447Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000366 in 1,614,044 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M4447V) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 3.94

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]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_206933.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-215674572-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 554155.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=6, Likely_pathogenic=2, Pathogenic=1}.
• PP5: Variant 1-215674572-T-A is Pathogenic according to our data. Variant chr1-215674572-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 930727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.1367209).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4	c.13339A>T	p.Met4447Leu	missense_variant	63/72	ENST00000307340.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8	c.13339A>T	p.Met4447Leu	missense_variant	63/72	1	NM_206933.4	P1
USH2A	ENST00000674083.1	c.13339A>T	p.Met4447Leu	missense_variant	63/73

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152172 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: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250650 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135442

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000925

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000363 AC: 53 AN: 1461872 Hom.: 0 Cov.: 31 AF XY: 0.0000399 AC XY: 29 AN XY: 727232

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000393

Gnomad4 NFE exome AF: 0.0000270

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152172 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74338

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Usher syndrome type 2A Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 04, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 19, 2020	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP3. This variant was detected in homozygous state. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Oct 23, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	19
Dann	Benign	0.87
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.069
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.65	T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	0.97	D;D
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.095
Sift	Benign	0.21	T
Sift4G	Uncertain	0.040	D
Polyphen		0.062	B
Vest4		0.26
MutPred		0.55		Loss of disorder (P = 0.1053);
MVP		0.62
MPC		0.031
ClinPred		0.25	T
GERP RS		4.7
Varity_R		0.28
gMVP		0.35

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

Publications

LitVar

Other links and lift over

dbSNP: rs139474806; hg19: chr1-215847914;