rs34077456

Variant names:

• chr11-17501084-C-A
• rs34077456
• NM_153676.4:c.2347G>T

Your query was ambiguous. Multiple possible variants found:

• chr11-17501084-C-A
• chr11-17501084-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_153676.4(USH1C):​c.2347G>T​(p.Ala783Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00227 in 1,614,038 control chromosomes in the GnomAD database, including 71 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A783V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.012 (39 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (32 hom.)
• Consequence: USH1C NM_153676.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.68
• Publications: 5 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 (MetaRNN=0.0063123703).
• BP6: Variant 11-17501084-C-A is Benign according to our data. Variant chr11-17501084-C-A is described in ClinVar as Benign. ClinVar VariationId is 47999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0122 (1858/152350) while in subpopulation AFR AF = 0.0425 (1768/41576). AF 95% confidence interval is 0.0409. There are 39 homozygotes in GnomAd4. There are 888 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 39 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.2347G>T	p.Ala783Ser	missense	Exon 23 of 27	NP_710142.1	Q9Y6N9-5
	USH1C	NM_005709.4	MANE Plus Clinical	c.1447G>T	p.Ala483Ser	missense	Exon 18 of 21	NP_005700.2	A0A0S2Z4U9
	USH1C	NM_001440679.1		c.1633G>T	p.Ala545Ser	missense	Exon 19 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.2347G>T	p.Ala783Ser	missense	Exon 23 of 27	ENSP00000005226.7	Q9Y6N9-5
	USH1C	ENST00000318024.9	TSL:1 MANE Plus Clinical	c.1447G>T	p.Ala483Ser	missense	Exon 18 of 21	ENSP00000317018.4	Q9Y6N9-1
	USH1C	ENST00000527020.5	TSL:1	c.1390G>T	p.Ala464Ser	missense	Exon 17 of 20	ENSP00000436934.1	Q9Y6N9-4

Frequencies

GnomAD3 genomes AF: 0.0122 AC: 1853 AN: 152232 Hom.: 39 Cov.: 33

Gnomad AFR AF: 0.0425

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00347

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: 0.000147

Gnomad OTH AF: 0.0129

GnomAD2 exomes AF: 0.00316 AC: 794 AN: 250894 AF XY: 0.00228

Gnomad AFR exome AF: 0.0442

Gnomad AMR exome AF: 0.00176

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000705

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00124 AC: 1807 AN: 1461688 Hom.: 32 Cov.: 31 AF XY: 0.00104 AC XY: 756 AN XY: 727148

African (AFR) AF: 0.0436 AC: 1459 AN: 33446

American (AMR) AF: 0.00217 AC: 97 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53328

Middle Eastern (MID) AF: 0.00260 AC: 15 AN: 5768

European-Non Finnish (NFE) AF: 0.0000594 AC: 66 AN: 1111964

Other (OTH) AF: 0.00275 AC: 166 AN: 60396

GnomAD4 genome AF: 0.0122 AC: 1858 AN: 152350 Hom.: 39 Cov.: 33 AF XY: 0.0119 AC XY: 888 AN XY: 74506

African (AFR) AF: 0.0425 AC: 1768 AN: 41576

American (AMR) AF: 0.00346 AC: 53 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68038

Other (OTH) AF: 0.0128 AC: 27 AN: 2112

Alfa AF: 0.00385 Hom.: 35

Bravo AF: 0.0139

ESP6500AA AF: 0.0443 AC: 195

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00405 AC: 492

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.056	T
Eigen	Benign	-0.15
Eigen_PC	Benign	0.069
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0063	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.080	N
PhyloP100		2.7
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.041
Sift	Benign	0.47	T
Sift4G	Benign	0.54	T
Polyphen		0.0	B
Vest4		0.21
MVP		0.31
MPC		0.093
ClinPred		0.015	T
GERP RS		5.3
Varity_R		0.24
gMVP		0.48
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs34077456; hg19: chr11-17522631; COSMIC: COSV99040696; COSMIC: COSV99040696;