rs146333270

Positions:

• chr11-17510505-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_153676.4(USH1C):​c.1430G>A​(p.Arg477Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000529 in 1,613,896 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R477G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00054 (0 hom.)
• Consequence: USH1C NM_153676.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 7.22

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40767193).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH1C	NM_153676.4	c.1430G>A	p.Arg477Gln	missense_variant	17/27	ENST00000005226.12
USH1C	NM_005709.4	c.1284+6896G>A		intron_variant		ENST00000318024.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH1C	ENST00000005226.12	c.1430G>A	p.Arg477Gln	missense_variant	17/27	5	NM_153676.4
USH1C	ENST00000318024.9	c.1284+6896G>A		intron_variant		1	NM_005709.4	P1

Frequencies

GnomAD3 genomes AF: 0.000401 AC: 61 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

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: 0.000750

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000286 AC: 72 AN: 251326 Hom.: 0 AF XY: 0.000258 AC XY: 35 AN XY: 135840

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000431

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000543 AC: 793 AN: 1461598 Hom.: 0 Cov.: 31 AF XY: 0.000503 AC XY: 366 AN XY: 727106

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000403

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000659

Gnomad4 OTH exome AF: 0.000530

GnomAD4 genome AF: 0.000401 AC: 61 AN: 152298 Hom.: 0 Cov.: 32 AF XY: 0.000349 AC XY: 26 AN XY: 74476

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000750

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000672 Hom.: 0

Bravo AF: 0.000389

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000466 AC: 4

ExAC AF: 0.000288 AC: 35

EpiCase AF: 0.000327

EpiControl AF: 0.000711

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 04, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 03, 2017	The p.Arg477Gln variant (rs146333270) has been reported as a ‘probably neutral variant’ in at least one individual with Usher syndrome; however, inheritance and specific clinical information were not reported (Le Quesne Stabej 2012). The p.Arg477Gln variant is listed in the Genome Aggregation Database (gnomAD) browser with an overall allele frequency of 0.028% (identified in 77 out of 277,120 chromosomes), and is classified as a variant of uncertain significance in ClinVar (Variant ID: 47979). The arginine at codon 477 is moderately conserved considering 12 species (Alamut software v2.10.0), and computational analyses suggest that this variant affects the structure/function of the USH1C protein (SIFT: damaging, PolyPhen2: probably damaging, MutationTaster: disease causing). However, based on the available information, the clinical significance of the p.Arg477Gln variant cannot be determined with certainty. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 24, 2018

The p.Arg477Gln variant in USH1C has been previously reported by our laboratory in the heterozygous state in two individuals with hearing loss, one of whom har bored two pathogenic variants in another gene. This variant has been identified in 77/277120 of the total chromosomes by the Genome Aggregation Database (gnomAD , http://gnomad.broadinstitute.org/; dbSNP rs146333270). Although this variant h as been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation analysis suggest that the p.Arg477Gln variant may impact the protein, though this inform ation is not predictive enough to determine pathogenicity. In summary, the clini cal significance of the p.Arg477Gln variant is uncertain. ACMG/AMP Criteria appl ied: PM2_Supporting; PP3. -

Hearing impairment Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center

Apr 12, 2021

PM2_Supporting, PP3_Supporting -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	30
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-0.63	T
MutationTaster	Benign	0.99	D;D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.26
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.086	T
Vest4		0.76
MVP		0.56
MPC		0.40
ClinPred		0.19	T
GERP RS		5.9
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs146333270; hg19: chr11-17532052;