11-17533565-T-C

Variant names:

• chr11-17533565-T-C
• rs2883581
• NM_153676.4:c.37-243A>G

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.37-243A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.561 in 613,440 control chromosomes in the GnomAD database, including 97,734 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.59 (26383 hom., cov: 32)
  • Exomes 𝑓: 0.55 (71351 hom.)
• Consequence: USH1C NM_153676.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.17
• Publications: 9 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, Unknown Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Usher syndrome type 1C

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

  Inheritance: Unknown, AR Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics
• 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=-0.91).
• BP6: Variant 11-17533565-T-C is Benign according to our data. Variant chr11-17533565-T-C is described in ClinVar as Benign. ClinVar VariationId is 678906.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.669 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH1C	NM_153676.4	MANE Select	c.37-243A>G		intron	N/A	NP_710142.1	Q9Y6N9-5
	USH1C	NM_005709.4	MANE Plus Clinical	c.37-243A>G		intron	N/A	NP_005700.2	A0A0S2Z4U9
	USH1C	NM_001440679.1		c.69+154A>G		intron	N/A	NP_001427608.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH1C	ENST00000005226.12	TSL:5 MANE Select	c.37-243A>G		intron	N/A	ENSP00000005226.7	Q9Y6N9-5
	USH1C	ENST00000318024.9	TSL:1 MANE Plus Clinical	c.37-243A>G		intron	N/A	ENSP00000317018.4	Q9Y6N9-1
	USH1C	ENST00000527020.5	TSL:1	c.37-243A>G		intron	N/A	ENSP00000436934.1	Q9Y6N9-4

Frequencies

GnomAD3 genomes AF: 0.585 AC: 88925 AN: 151936 Hom.: 26358 Cov.: 32

Gnomad AFR AF: 0.676

Gnomad AMI AF: 0.373

Gnomad AMR AF: 0.541

Gnomad ASJ AF: 0.558

Gnomad EAS AF: 0.582

Gnomad SAS AF: 0.598

Gnomad FIN AF: 0.647

Gnomad MID AF: 0.595

Gnomad NFE AF: 0.534

Gnomad OTH AF: 0.573

GnomAD4 exome AF: 0.553 AC: 255245 AN: 461388 Hom.: 71351 Cov.: 0 AF XY: 0.554 AC XY: 136139 AN XY: 245700

African (AFR) AF: 0.678 AC: 9336 AN: 13776

American (AMR) AF: 0.506 AC: 14580 AN: 28830

Ashkenazi Jewish (ASJ) AF: 0.553 AC: 8340 AN: 15084

East Asian (EAS) AF: 0.577 AC: 16636 AN: 28808

South Asian (SAS) AF: 0.598 AC: 30834 AN: 51528

European-Finnish (FIN) AF: 0.611 AC: 16946 AN: 27744

Middle Eastern (MID) AF: 0.589 AC: 1220 AN: 2072

European-Non Finnish (NFE) AF: 0.533 AC: 142668 AN: 267500

Other (OTH) AF: 0.564 AC: 14685 AN: 26046

GnomAD4 genome AF: 0.585 AC: 88992 AN: 152052 Hom.: 26383 Cov.: 32 AF XY: 0.588 AC XY: 43687 AN XY: 74328

African (AFR) AF: 0.676 AC: 28025 AN: 41482

American (AMR) AF: 0.541 AC: 8271 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.558 AC: 1934 AN: 3466

East Asian (EAS) AF: 0.583 AC: 3001 AN: 5150

South Asian (SAS) AF: 0.598 AC: 2884 AN: 4820

European-Finnish (FIN) AF: 0.647 AC: 6844 AN: 10586

Middle Eastern (MID) AF: 0.592 AC: 174 AN: 294

European-Non Finnish (NFE) AF: 0.534 AC: 36310 AN: 67950

Other (OTH) AF: 0.573 AC: 1210 AN: 2112

Alfa AF: 0.549 Hom.: 12704

Bravo AF: 0.584

Asia WGS AF: 0.612 AC: 2130 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.13
DANN	Benign	0.44
PhyloP100		-2.2
PromoterAI		-0.0072	Neutral
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: rs2883581; hg19: chr11-17555112; COSMIC: COSV50016308; COSMIC: COSV50016308;