11-17521325-G-C

Position:

• chr11-17521325-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_153676.4(USH1C):​c.1085+21C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.472 in 1,611,358 control chromosomes in the GnomAD database, including 182,507 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (14402 hom., cov: 32)
  • Exomes 𝑓: 0.48 (168105 hom.)
• Consequence: USH1C NM_153676.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.38

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 11-17521325-G-C is Benign according to our data. Variant chr11-17521325-G-C is described in ClinVar as [Benign]. Clinvar id is 47973.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-17521325-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.609 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH1C	NM_005709.4	c.1085+21C>G		intron_variant		ENST00000318024.9
USH1C	NM_153676.4	c.1085+21C>G		intron_variant		ENST00000005226.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH1C	ENST00000005226.12	c.1085+21C>G		intron_variant		5	NM_153676.4
USH1C	ENST00000318024.9	c.1085+21C>G		intron_variant		1	NM_005709.4	P1

Frequencies

GnomAD3 genomes AF: 0.427 AC: 64906 AN: 151872 Hom.: 14390 Cov.: 32

Gnomad AFR AF: 0.297

Gnomad AMI AF: 0.596

Gnomad AMR AF: 0.462

Gnomad ASJ AF: 0.424

Gnomad EAS AF: 0.627

Gnomad SAS AF: 0.464

Gnomad FIN AF: 0.432

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.479

Gnomad OTH AF: 0.413

GnomAD3 exomes AF: 0.468 AC: 117633 AN: 251476 Hom.: 28287 AF XY: 0.467 AC XY: 63463 AN XY: 135912

Gnomad AFR exome AF: 0.290

Gnomad AMR exome AF: 0.499

Gnomad ASJ exome AF: 0.421

Gnomad EAS exome AF: 0.627

Gnomad SAS exome AF: 0.456

Gnomad FIN exome AF: 0.436

Gnomad NFE exome AF: 0.472

Gnomad OTH exome AF: 0.447

GnomAD4 exome AF: 0.477 AC: 695465 AN: 1459368 Hom.: 168105 Cov.: 35 AF XY: 0.476 AC XY: 345728 AN XY: 726156

Gnomad4 AFR exome AF: 0.283

Gnomad4 AMR exome AF: 0.494

Gnomad4 ASJ exome AF: 0.418

Gnomad4 EAS exome AF: 0.634

Gnomad4 SAS exome AF: 0.454

Gnomad4 FIN exome AF: 0.440

Gnomad4 NFE exome AF: 0.482

Gnomad4 OTH exome AF: 0.464

GnomAD4 genome AF: 0.427 AC: 64943 AN: 151990 Hom.: 14402 Cov.: 32 AF XY: 0.430 AC XY: 31939 AN XY: 74282

Gnomad4 AFR AF: 0.296

Gnomad4 AMR AF: 0.462

Gnomad4 ASJ AF: 0.424

Gnomad4 EAS AF: 0.627

Gnomad4 SAS AF: 0.464

Gnomad4 FIN AF: 0.432

Gnomad4 NFE AF: 0.479

Gnomad4 OTH AF: 0.417

Alfa AF: 0.379 Hom.: 1795

Bravo AF: 0.423

Asia WGS AF: 0.528 AC: 1833 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 24, 2009	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2018	- -

Autosomal recessive nonsyndromic hearing loss 18A Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Usher syndrome type 1C Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.040
DANN	Benign	0.45

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: rs2240488; hg19: chr11-17542872;