11-17531558-G-A

Variant names:

• chr11-17531558-G-A
• rs2041027
• NM_153676.4:c.105-16C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_153676.4(USH1C):​c.105-16C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.414 in 1,611,078 control chromosomes in the GnomAD database, including 138,990 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (13292 hom., cov: 32)
  • Exomes 𝑓: 0.41 (125698 hom.)
• Consequence: USH1C NM_153676.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.379
• Publications: 16 publications found

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 Gene-Disease associations (from GenCC):

• Usher syndrome type 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Usher syndrome type 1C

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, PanelApp Australia
• autosomal recessive nonsyndromic hearing loss 18A

  Inheritance: AR, Unknown Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 11-17531558-G-A is Benign according to our data. Variant chr11-17531558-G-A is described in ClinVar as Benign. ClinVar VariationId is 47972.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.495 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153676.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH1C	NM_153676.4	MANE Select	c.105-16C>T		intron	N/A	NP_710142.1
	USH1C	NM_005709.4	MANE Plus Clinical	c.105-16C>T		intron	N/A	NP_005700.2
	USH1C	NM_001440679.1		c.138-16C>T		intron	N/A	NP_001427608.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH1C	ENST00000005226.12	TSL:5 MANE Select	c.105-16C>T		intron	N/A	ENSP00000005226.7
	USH1C	ENST00000318024.9	TSL:1 MANE Plus Clinical	c.105-16C>T		intron	N/A	ENSP00000317018.4
	USH1C	ENST00000527020.5	TSL:1	c.105-16C>T		intron	N/A	ENSP00000436934.1

Frequencies

GnomAD3 genomes AF: 0.417 AC: 63368 AN: 151836 Hom.: 13285 Cov.: 32

Gnomad AFR AF: 0.395

Gnomad AMI AF: 0.351

Gnomad AMR AF: 0.426

Gnomad ASJ AF: 0.470

Gnomad EAS AF: 0.511

Gnomad SAS AF: 0.333

Gnomad FIN AF: 0.498

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.414

Gnomad OTH AF: 0.424

GnomAD2 exomes AF: 0.420 AC: 104268 AN: 248282 AF XY: 0.416

Gnomad AFR exome AF: 0.394

Gnomad AMR exome AF: 0.407

Gnomad ASJ exome AF: 0.460

Gnomad EAS exome AF: 0.512

Gnomad FIN exome AF: 0.489

Gnomad NFE exome AF: 0.420

Gnomad OTH exome AF: 0.435

GnomAD4 exome AF: 0.413 AC: 602910 AN: 1459122 Hom.: 125698 Cov.: 56 AF XY: 0.411 AC XY: 298527 AN XY: 725838

African (AFR) AF: 0.396 AC: 13248 AN: 33440

American (AMR) AF: 0.411 AC: 18373 AN: 44652

Ashkenazi Jewish (ASJ) AF: 0.468 AC: 12228 AN: 26124

East Asian (EAS) AF: 0.521 AC: 20684 AN: 39684

South Asian (SAS) AF: 0.333 AC: 28658 AN: 86082

European-Finnish (FIN) AF: 0.487 AC: 25577 AN: 52502

Middle Eastern (MID) AF: 0.456 AC: 2163 AN: 4742

European-Non Finnish (NFE) AF: 0.411 AC: 457030 AN: 1111634

Other (OTH) AF: 0.414 AC: 24949 AN: 60262

GnomAD4 genome AF: 0.417 AC: 63392 AN: 151956 Hom.: 13292 Cov.: 32 AF XY: 0.417 AC XY: 30965 AN XY: 74268

African (AFR) AF: 0.394 AC: 16319 AN: 41426

American (AMR) AF: 0.426 AC: 6504 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.470 AC: 1629 AN: 3464

East Asian (EAS) AF: 0.511 AC: 2634 AN: 5150

South Asian (SAS) AF: 0.333 AC: 1606 AN: 4816

European-Finnish (FIN) AF: 0.498 AC: 5258 AN: 10566

Middle Eastern (MID) AF: 0.442 AC: 130 AN: 294

European-Non Finnish (NFE) AF: 0.414 AC: 28101 AN: 67946

Other (OTH) AF: 0.422 AC: 892 AN: 2114

Alfa AF: 0.418 Hom.: 21214

Bravo AF: 0.416

Asia WGS AF: 0.403 AC: 1402 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 24, 2009

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 21, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Autosomal recessive nonsyndromic hearing loss 18A Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Usher syndrome type 1C Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.4
DANN	Benign	0.57
PhyloP100		0.38
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2041027; hg19: chr11-17553105; COSMIC: COSV50038647;