rs1055581

Variant names:

• chr11-17494121-T-C
• rs1055581
• NM_153676.4:c.*211A>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.*211A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.445 in 612,558 control chromosomes in the GnomAD database, including 61,875 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (15358 hom., cov: 32)
  • Exomes 𝑓: 0.44 (46517 hom.)
• Consequence: USH1C NM_153676.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -6.07
• Publications: 17 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=-0.98).
• BP6: Variant 11-17494121-T-C is Benign according to our data. Variant chr11-17494121-T-C is described in ClinVar as Benign. ClinVar VariationId is 303796.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.465 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.*211A>G		3_prime_UTR	Exon 27 of 27	NP_710142.1	Q9Y6N9-5
	USH1C	NM_005709.4	MANE Plus Clinical	c.*243A>G		3_prime_UTR	Exon 21 of 21	NP_005700.2	A0A0S2Z4U9
	USH1C	NM_001440679.1		c.*243A>G		3_prime_UTR	Exon 22 of 22	NP_001427608.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH1C	ENST00000005226.12	TSL:5 MANE Select	c.*211A>G		3_prime_UTR	Exon 27 of 27	ENSP00000005226.7	Q9Y6N9-5
	USH1C	ENST00000318024.9	TSL:1 MANE Plus Clinical	c.*243A>G		3_prime_UTR	Exon 21 of 21	ENSP00000317018.4	Q9Y6N9-1
	USH1C	ENST00000527020.5	TSL:1	c.*243A>G		3_prime_UTR	Exon 20 of 20	ENSP00000436934.1	Q9Y6N9-4

Frequencies

GnomAD3 genomes AF: 0.447 AC: 67730 AN: 151572 Hom.: 15343 Cov.: 32

Gnomad AFR AF: 0.454

Gnomad AMI AF: 0.426

Gnomad AMR AF: 0.369

Gnomad ASJ AF: 0.486

Gnomad EAS AF: 0.295

Gnomad SAS AF: 0.380

Gnomad FIN AF: 0.481

Gnomad MID AF: 0.361

Gnomad NFE AF: 0.469

Gnomad OTH AF: 0.447

GnomAD4 exome AF: 0.444 AC: 204515 AN: 460864 Hom.: 46517 Cov.: 5 AF XY: 0.440 AC XY: 107472 AN XY: 244234

African (AFR) AF: 0.460 AC: 5792 AN: 12600

American (AMR) AF: 0.338 AC: 7391 AN: 21882

Ashkenazi Jewish (ASJ) AF: 0.474 AC: 6677 AN: 14072

East Asian (EAS) AF: 0.304 AC: 9093 AN: 29882

South Asian (SAS) AF: 0.382 AC: 18148 AN: 47552

European-Finnish (FIN) AF: 0.466 AC: 15722 AN: 33758

Middle Eastern (MID) AF: 0.409 AC: 793 AN: 1938

European-Non Finnish (NFE) AF: 0.473 AC: 129530 AN: 273600

Other (OTH) AF: 0.444 AC: 11369 AN: 25580

GnomAD4 genome AF: 0.447 AC: 67774 AN: 151694 Hom.: 15358 Cov.: 32 AF XY: 0.446 AC XY: 33044 AN XY: 74134

African (AFR) AF: 0.454 AC: 18781 AN: 41354

American (AMR) AF: 0.369 AC: 5621 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.486 AC: 1681 AN: 3462

East Asian (EAS) AF: 0.295 AC: 1518 AN: 5146

South Asian (SAS) AF: 0.381 AC: 1831 AN: 4812

European-Finnish (FIN) AF: 0.481 AC: 5064 AN: 10518

Middle Eastern (MID) AF: 0.364 AC: 107 AN: 294

European-Non Finnish (NFE) AF: 0.469 AC: 31844 AN: 67844

Other (OTH) AF: 0.445 AC: 939 AN: 2108

Alfa AF: 0.456 Hom.: 25437

Bravo AF: 0.439

Asia WGS AF: 0.357 AC: 1241 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	Usher syndrome type 1C (2)
-	-	1	Autosomal recessive nonsyndromic hearing loss 18A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.032
DANN	Benign	0.51
PhyloP100		-6.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1055581; hg19: chr11-17515668; COSMIC: COSV50046005; COSMIC: COSV50046005;