rs41282942

Variant names:

• chr11-17531160-C-A
• rs41282942
• NM_153676.4:c.381G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_153676.4(USH1C):​c.381G>T​(p.Gly127Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00374 in 1,614,094 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0029 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0038 (16 hom.)
• Consequence: USH1C NM_153676.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: 0.148
• Publications: 2 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.22).
• BP6: Variant 11-17531160-C-A is Benign according to our data. Variant chr11-17531160-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 48014.
• BP7: Synonymous conserved (PhyloP=0.148 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0029 (442/152318) while in subpopulation NFE AF = 0.00487 (331/68012). AF 95% confidence interval is 0.00443. There are 2 homozygotes in GnomAd4. There are 193 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR,Unknown gene

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.381G>T	p.Gly127Gly	synonymous	Exon 4 of 27	NP_710142.1	Q9Y6N9-5
	USH1C	NM_005709.4	MANE Plus Clinical	c.381G>T	p.Gly127Gly	synonymous	Exon 4 of 21	NP_005700.2	A0A0S2Z4U9
	USH1C	NM_001440679.1		c.414G>T	p.Gly138Gly	synonymous	Exon 4 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.381G>T	p.Gly127Gly	synonymous	Exon 4 of 27	ENSP00000005226.7	Q9Y6N9-5
	USH1C	ENST00000318024.9	TSL:1 MANE Plus Clinical	c.381G>T	p.Gly127Gly	synonymous	Exon 4 of 21	ENSP00000317018.4	Q9Y6N9-1
	USH1C	ENST00000527020.5	TSL:1	c.381G>T	p.Gly127Gly	synonymous	Exon 4 of 20	ENSP00000436934.1	Q9Y6N9-4

Frequencies

GnomAD3 genomes AF: 0.00290 AC: 442 AN: 152200 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000651

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00547

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00487

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00318 AC: 799 AN: 250874 AF XY: 0.00351

Gnomad AFR exome AF: 0.000496

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.00576

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00143

Gnomad NFE exome AF: 0.00495

Gnomad OTH exome AF: 0.00506

GnomAD4 exome AF: 0.00383 AC: 5602 AN: 1461776 Hom.: 16 Cov.: 31 AF XY: 0.00382 AC XY: 2779 AN XY: 727204

African (AFR) AF: 0.000538 AC: 18 AN: 33476

American (AMR) AF: 0.00165 AC: 74 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00559 AC: 146 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00189 AC: 163 AN: 86258

European-Finnish (FIN) AF: 0.00182 AC: 97 AN: 53330

Middle Eastern (MID) AF: 0.00903 AC: 52 AN: 5760

European-Non Finnish (NFE) AF: 0.00434 AC: 4826 AN: 1112010

Other (OTH) AF: 0.00374 AC: 226 AN: 60386

GnomAD4 genome AF: 0.00290 AC: 442 AN: 152318 Hom.: 2 Cov.: 33 AF XY: 0.00259 AC XY: 193 AN XY: 74494

African (AFR) AF: 0.000649 AC: 27 AN: 41582

American (AMR) AF: 0.00229 AC: 35 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00547 AC: 19 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4828

European-Finnish (FIN) AF: 0.00141 AC: 15 AN: 10622

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00487 AC: 331 AN: 68012

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00401 Hom.: 2

Bravo AF: 0.00289

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00622

EpiControl AF: 0.00599

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	not specified (4)
-	1	1	Usher syndrome type 1C (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.22
CADD	Benign	6.0
DANN	Benign	0.75
PhyloP100		0.15
Mutation Taster		=98/2	polymorphism

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: rs41282942; hg19: chr11-17552707;