rs78509055

Positions:

• chr11-17495685-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_153676.4(USH1C):​c.2547-8A>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00115 in 1,613,868 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0066 (11 hom., cov: 33)
  • Exomes 𝑓: 0.00059 (12 hom.)
• Consequence: USH1C NM_153676.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00002404
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.05

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=-0.88).
• BP6: Variant 11-17495685-T-C is Benign according to our data. Variant chr11-17495685-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 178560.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-17495685-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00658 (1001/152224) while in subpopulation AFR AF= 0.0226 (941/41550). AF 95% confidence interval is 0.0214. There are 11 homozygotes in gnomad4. There are 474 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH1C	NM_005709.4	c.1646+1073A>G		intron_variant		ENST00000318024.9
USH1C	NM_153676.4	c.2547-8A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000005226.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH1C	ENST00000005226.12	c.2547-8A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_153676.4
USH1C	ENST00000318024.9	c.1646+1073A>G		intron_variant		1	NM_005709.4	P1

Frequencies

GnomAD3 genomes AF: 0.00654 AC: 995 AN: 152106 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.0226

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

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: 0.0000294

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00179 AC: 450 AN: 251350 Hom.: 0 AF XY: 0.00134 AC XY: 182 AN XY: 135862

Gnomad AFR exome AF: 0.0244

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000588 AC: 859 AN: 1461644 Hom.: 12 Cov.: 31 AF XY: 0.000503 AC XY: 366 AN XY: 727140

Gnomad4 AFR exome AF: 0.0200

Gnomad4 AMR exome AF: 0.00148

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.00171

GnomAD4 genome AF: 0.00658 AC: 1001 AN: 152224 Hom.: 11 Cov.: 33 AF XY: 0.00637 AC XY: 474 AN XY: 74398

Gnomad4 AFR AF: 0.0226

Gnomad4 AMR AF: 0.00307

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00361 Hom.: 3

Bravo AF: 0.00756

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 13, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 20, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Oct 03, 2022	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 30, 2012

2547-8A>G in Intron 25 of USH1C: This variant is not expected to have clinical s ignificance because it has been identified in 1.9% (72/3738) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs78509055). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.35
DANN	Benign	0.40

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000024
dbscSNV1_RF	Benign	0.0
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: rs78509055; hg19: chr11-17517232;