rs1849167922

Variant names:

• chr11-17494365-C-T
• rs1849167922
• NM_005709.4:c.1658G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The NM_005709.4(USH1C):​c.1658G>A​(p.Ter553Ter) variant causes a stop retained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000025 in 1,602,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: USH1C NM_005709.4 stop_retained
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0670
• Publications: 0 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 11-17494365-C-T is Benign according to our data. Variant chr11-17494365-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1141175.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.067 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005709.4. 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_005709.4	MANE Plus Clinical	c.1658G>A	p.Ter553Ter	stop_retained	Exon 21 of 21	NP_005700.2	A0A0S2Z4U9
	USH1C	NM_153676.4	MANE Select	c.2667G>A	p.Leu889Leu	synonymous	Exon 27 of 27	NP_710142.1	Q9Y6N9-5
	USH1C	NM_001440679.1		c.1844G>A	p.Ter615Ter	stop_retained	Exon 22 of 22	NP_001427608.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH1C	ENST00000318024.9	TSL:1 MANE Plus Clinical	c.1658G>A	p.Ter553Ter	stop_retained	Exon 21 of 21	ENSP00000317018.4	Q9Y6N9-1
	USH1C	ENST00000527020.5	TSL:1	c.1601G>A	p.Ter534Ter	stop_retained	Exon 20 of 20	ENSP00000436934.1	Q9Y6N9-4
	USH1C	ENST00000527720.5	TSL:1	c.1565G>A	p.Ter522Ter	stop_retained	Exon 20 of 20	ENSP00000432944.1	Q9Y6N9-2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152202 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1450644 Hom.: 0 Cov.: 34 AF XY: 0.00000278 AC XY: 2 AN XY: 720446

African (AFR) AF: 0.0000301 AC: 1 AN: 33244

American (AMR) AF: 0.00 AC: 0 AN: 43462

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25920

East Asian (EAS) AF: 0.00 AC: 0 AN: 39362

South Asian (SAS) AF: 0.00 AC: 0 AN: 83894

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52714

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1106304

Other (OTH) AF: 0.00 AC: 0 AN: 60018

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152202 Hom.: 0 Cov.: 34 AF XY: 0.0000134 AC XY: 1 AN XY: 74358

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	4.2
DANN	Benign	0.61
PhyloP100		-0.067

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs1849167922; hg19: chr11-17515912;