rs139996942

Positions:

• chr11-17509510-C-A
• chr11-17509510-C-G
• chr11-17509510-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM5 BP4_Strong BP6_Very_Strong BA1

The NM_153676.4(USH1C):​c.1859G>T​(p.Arg620Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00474 in 581,820 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R620C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.039 (18 hom., cov: 0)
  • Exomes 𝑓: 0.0025 (25 hom.)
• Consequence: USH1C NM_153676.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.34

Genes affected

USH1C (HGNC:12597): (USH1 protein network component harmonin) This gene encodes a scaffold protein that functions in the assembly of Usher protein complexes. The protein contains PDZ domains, a coiled-coil region with a bipartite nuclear localization signal and a PEST degradation sequence. Defects in this gene are the cause of Usher syndrome type 1C and non-syndromic sensorineural deafness autosomal recessive type 18. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]

USH1C (HGNC:):

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-17509511-G-A is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.004986495).
• BP6: Variant 11-17509510-C-A is Benign according to our data. Variant chr11-17509510-C-A is described in ClinVar as [Benign]. Clinvar id is 166377.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-17509510-C-A is described in Lovd as [Pathogenic].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.12 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH1C	NM_153676.4	c.1859G>T	p.Arg620Leu	missense_variant	18/27	ENST00000005226.12	NP_710142.1
USH1C	NM_005709.4	c.1285-7530G>T		intron_variant		ENST00000318024.9	NP_005700.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH1C	ENST00000005226.12	c.1859G>T	p.Arg620Leu	missense_variant	18/27	5	NM_153676.4	ENSP00000005226.7
USH1C	ENST00000318024.9	c.1285-7530G>T		intron_variant		1	NM_005709.4	ENSP00000317018.4

Frequencies

GnomAD3 genomes AF: 0.0388 AC: 1366 AN: 35200 Hom.: 17 Cov.: 0

Gnomad AFR AF: 0.125

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0156

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000969

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.0529

GnomAD3 exomes AF: 0.00276 AC: 631 AN: 228446 Hom.: 9 AF XY: 0.00210 AC XY: 260 AN XY: 124042

Gnomad AFR exome AF: 0.0364

Gnomad AMR exome AF: 0.00208

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000222

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000188

Gnomad OTH exome AF: 0.000553

GnomAD4 exome AF: 0.00254 AC: 1388 AN: 546578 Hom.: 25 Cov.: 34 AF XY: 0.00212 AC XY: 592 AN XY: 279170

Gnomad4 AFR exome AF: 0.0705

Gnomad4 AMR exome AF: 0.00259

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000303

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000235

Gnomad4 OTH exome AF: 0.00535

GnomAD4 genome AF: 0.0389 AC: 1370 AN: 35242 Hom.: 18 Cov.: 0 AF XY: 0.0382 AC XY: 642 AN XY: 16810

Gnomad4 AFR AF: 0.125

Gnomad4 AMR AF: 0.0156

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000967

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.0519

Alfa AF: 0.00117 Hom.: 3

Bravo AF: 0.0106

ESP6500AA AF: 0.0316 AC: 139

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00330 AC: 400

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Arg620Leu in Exon 18 of USH1C: This variant is not expected to have clinical sig nificance because it has been identified in 2.9% (110/3738) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs139996942). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 27, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 20, 2016	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 08, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	22
DANN	Uncertain	1.0
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0050	T
MetaSVM	Benign	-1.0	T
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.99	N
REVEL	Benign	0.23
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.13	T
Vest4		0.66
MVP		0.58
MPC		0.080
ClinPred		0.016	T
GERP RS		5.9
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs139996942; hg19: chr11-17531057;