11-17494286-A-G

Variant names:

• chr11-17494286-A-G
• rs1055574
• NM_153676.4:c.*46T>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.*46T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.456 in 1,591,812 control chromosomes in the GnomAD database, including 167,694 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (14730 hom., cov: 33)
  • Exomes 𝑓: 0.46 (152964 hom.)
• Consequence: USH1C NM_153676.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.0870
• Publications: 21 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 1C

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine, G2P
• Usher syndrome type 1

  Inheritance: Unknown, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• autosomal recessive nonsyndromic hearing loss 18A

  Inheritance: AR, Unknown Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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=-0.9).
• BP6: Variant 11-17494286-A-G is Benign according to our data. Variant chr11-17494286-A-G is described in ClinVar as Benign. ClinVar VariationId is 262730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.466 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.*46T>C		3_prime_UTR	Exon 27 of 27	NP_710142.1	Q9Y6N9-5
	USH1C	NM_005709.4	MANE Plus Clinical	c.*78T>C		3_prime_UTR	Exon 21 of 21	NP_005700.2	A0A0S2Z4U9
	USH1C	NM_001440679.1		c.*78T>C		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.*46T>C		3_prime_UTR	Exon 27 of 27	ENSP00000005226.7	Q9Y6N9-5
	USH1C	ENST00000318024.9	TSL:1 MANE Plus Clinical	c.*78T>C		3_prime_UTR	Exon 21 of 21	ENSP00000317018.4	Q9Y6N9-1
	USH1C	ENST00000527020.5	TSL:1	c.*78T>C		3_prime_UTR	Exon 20 of 20	ENSP00000436934.1	Q9Y6N9-4

Frequencies

GnomAD3 genomes AF: 0.436 AC: 66227 AN: 151932 Hom.: 14720 Cov.: 33

Gnomad AFR AF: 0.412

Gnomad AMI AF: 0.426

Gnomad AMR AF: 0.367

Gnomad ASJ AF: 0.487

Gnomad EAS AF: 0.295

Gnomad SAS AF: 0.381

Gnomad FIN AF: 0.488

Gnomad MID AF: 0.361

Gnomad NFE AF: 0.470

Gnomad OTH AF: 0.432

GnomAD2 exomes AF: 0.423 AC: 92866 AN: 219628 AF XY: 0.427

Gnomad AFR exome AF: 0.413

Gnomad AMR exome AF: 0.320

Gnomad ASJ exome AF: 0.477

Gnomad EAS exome AF: 0.304

Gnomad FIN exome AF: 0.482

Gnomad NFE exome AF: 0.472

Gnomad OTH exome AF: 0.427

GnomAD4 exome AF: 0.458 AC: 659837 AN: 1439762 Hom.: 152964 Cov.: 32 AF XY: 0.457 AC XY: 326077 AN XY: 714094

African (AFR) AF: 0.408 AC: 13491 AN: 33046

American (AMR) AF: 0.322 AC: 13536 AN: 42026

Ashkenazi Jewish (ASJ) AF: 0.477 AC: 12286 AN: 25756

East Asian (EAS) AF: 0.303 AC: 11840 AN: 39062

South Asian (SAS) AF: 0.381 AC: 31583 AN: 82824

European-Finnish (FIN) AF: 0.475 AC: 24774 AN: 52160

Middle Eastern (MID) AF: 0.374 AC: 2089 AN: 5590

European-Non Finnish (NFE) AF: 0.476 AC: 523650 AN: 1099684

Other (OTH) AF: 0.446 AC: 26588 AN: 59614

GnomAD4 genome AF: 0.436 AC: 66266 AN: 152050 Hom.: 14730 Cov.: 33 AF XY: 0.435 AC XY: 32367 AN XY: 74322

African (AFR) AF: 0.412 AC: 17085 AN: 41480

American (AMR) AF: 0.367 AC: 5611 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.487 AC: 1689 AN: 3470

East Asian (EAS) AF: 0.295 AC: 1523 AN: 5158

South Asian (SAS) AF: 0.382 AC: 1839 AN: 4816

European-Finnish (FIN) AF: 0.488 AC: 5157 AN: 10562

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

European-Non Finnish (NFE) AF: 0.470 AC: 31959 AN: 67952

Other (OTH) AF: 0.431 AC: 908 AN: 2108

Alfa AF: 0.451 Hom.: 50437

Bravo AF: 0.425

Asia WGS AF: 0.354 AC: 1233 AN: 3478

ClinVar

ClinVar submissions

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)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.1
DANN	Benign	0.55
PhyloP100		-0.087
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: rs1055574; hg19: chr11-17515833; COSMIC: COSV50036203; COSMIC: COSV50036203;