11-17495688-A-G

Variant names:

• chr11-17495688-A-G
• rs10832795
• NM_153676.4:c.2547-11T>C

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.2547-11T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.408 in 1,613,404 control chromosomes in the GnomAD database, including 136,610 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (10581 hom., cov: 33)
  • Exomes 𝑓: 0.41 (126029 hom.)
• Consequence: USH1C NM_153676.4 intron
• Scores: Splicing: ADA: 0.0006627
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.81
• Publications: 11 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=-0.66).
• BP6: Variant 11-17495688-A-G is Benign according to our data. Variant chr11-17495688-A-G is described in ClinVar as Benign. ClinVar VariationId is 48008.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.425 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.2547-11T>C		intron	N/A	NP_710142.1
	USH1C	NM_005709.4	MANE Plus Clinical	c.1646+1070T>C		intron	N/A	NP_005700.2
	USH1C	NM_001440679.1		c.1832+1070T>C		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.2547-11T>C		intron	N/A	ENSP00000005226.7
	USH1C	ENST00000318024.9	TSL:1 MANE Plus Clinical	c.1646+1070T>C		intron	N/A	ENSP00000317018.4
	USH1C	ENST00000527020.5	TSL:1	c.1589+1070T>C		intron	N/A	ENSP00000436934.1

Frequencies

GnomAD3 genomes AF: 0.363 AC: 55137 AN: 152036 Hom.: 10586 Cov.: 33

Gnomad AFR AF: 0.235

Gnomad AMI AF: 0.350

Gnomad AMR AF: 0.428

Gnomad ASJ AF: 0.339

Gnomad EAS AF: 0.306

Gnomad SAS AF: 0.442

Gnomad FIN AF: 0.407

Gnomad MID AF: 0.386

Gnomad NFE AF: 0.419

Gnomad OTH AF: 0.356

GnomAD2 exomes AF: 0.410 AC: 103099 AN: 251188 AF XY: 0.412

Gnomad AFR exome AF: 0.227

Gnomad AMR exome AF: 0.508

Gnomad ASJ exome AF: 0.351

Gnomad EAS exome AF: 0.298

Gnomad FIN exome AF: 0.418

Gnomad NFE exome AF: 0.417

Gnomad OTH exome AF: 0.430

GnomAD4 exome AF: 0.412 AC: 602356 AN: 1461250 Hom.: 126029 Cov.: 36 AF XY: 0.413 AC XY: 300207 AN XY: 726960

African (AFR) AF: 0.225 AC: 7536 AN: 33474

American (AMR) AF: 0.502 AC: 22443 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.354 AC: 9260 AN: 26132

East Asian (EAS) AF: 0.306 AC: 12138 AN: 39692

South Asian (SAS) AF: 0.447 AC: 38523 AN: 86240

European-Finnish (FIN) AF: 0.419 AC: 22357 AN: 53336

Middle Eastern (MID) AF: 0.415 AC: 2394 AN: 5762

European-Non Finnish (NFE) AF: 0.417 AC: 463813 AN: 1111524

Other (OTH) AF: 0.396 AC: 23892 AN: 60374

GnomAD4 genome AF: 0.362 AC: 55146 AN: 152154 Hom.: 10581 Cov.: 33 AF XY: 0.362 AC XY: 26916 AN XY: 74382

African (AFR) AF: 0.235 AC: 9758 AN: 41480

American (AMR) AF: 0.429 AC: 6554 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.339 AC: 1177 AN: 3470

East Asian (EAS) AF: 0.306 AC: 1585 AN: 5184

South Asian (SAS) AF: 0.440 AC: 2124 AN: 4822

European-Finnish (FIN) AF: 0.407 AC: 4308 AN: 10592

Middle Eastern (MID) AF: 0.381 AC: 112 AN: 294

European-Non Finnish (NFE) AF: 0.419 AC: 28467 AN: 67998

Other (OTH) AF: 0.351 AC: 742 AN: 2112

Alfa AF: 0.381 Hom.: 3749

Bravo AF: 0.359

Asia WGS AF: 0.362 AC: 1259 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Jun 24, 2009

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Mar 03, 2015

GeneDx

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

Autosomal recessive nonsyndromic hearing loss 18A Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Usher syndrome type 1C Benign:1

Jul 10, 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	-0.66
CADD	Benign	12
DANN	Benign	0.58
PhyloP100		1.8
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00066
dbscSNV1_RF	Benign	0.074
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: rs10832795; hg19: chr11-17517235; COSMIC: COSV50013976; COSMIC: COSV50013976;