rs35336155

Variant names:

• chr11-17522857-C-G
• rs35336155
• NM_153676.4:c.946G>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_153676.4(USH1C):​c.946G>C​(p.Glu316Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000668 in 1,613,086 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E316E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0034 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00038 (6 hom.)
• Consequence: USH1C NM_153676.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 7.08
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008229464).
• BP6: Variant 11-17522857-C-G is Benign according to our data. Variant chr11-17522857-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 178643.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00341 (520/152290) while in subpopulation AFR AF = 0.0114 (473/41558). AF 95% confidence interval is 0.0105. There are 4 homozygotes in GnomAd4. There are 251 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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.946G>C	p.Glu316Gln	missense	Exon 12 of 27	NP_710142.1	Q9Y6N9-5
	USH1C	NM_005709.4	MANE Plus Clinical	c.946G>C	p.Glu316Gln	missense	Exon 12 of 21	NP_005700.2	A0A0S2Z4U9
	USH1C	NM_001440679.1		c.979G>C	p.Glu327Gln	missense	Exon 12 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.946G>C	p.Glu316Gln	missense	Exon 12 of 27	ENSP00000005226.7	Q9Y6N9-5
	USH1C	ENST00000318024.9	TSL:1 MANE Plus Clinical	c.946G>C	p.Glu316Gln	missense	Exon 12 of 21	ENSP00000317018.4	Q9Y6N9-1
	USH1C	ENST00000527020.5	TSL:1	c.889G>C	p.Glu297Gln	missense	Exon 11 of 20	ENSP00000436934.1	Q9Y6N9-4

Frequencies

GnomAD3 genomes AF: 0.00336 AC: 511 AN: 152172 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0112

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.000880 AC: 216 AN: 245344 AF XY: 0.000726

Gnomad AFR exome AF: 0.0125

Gnomad AMR exome AF: 0.000642

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000272

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000381 AC: 557 AN: 1460796 Hom.: 6 Cov.: 33 AF XY: 0.000332 AC XY: 241 AN XY: 726714

African (AFR) AF: 0.0128 AC: 430 AN: 33464

American (AMR) AF: 0.000605 AC: 27 AN: 44654

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86206

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52896

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5758

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111740

Other (OTH) AF: 0.00146 AC: 88 AN: 60278

GnomAD4 genome AF: 0.00341 AC: 520 AN: 152290 Hom.: 4 Cov.: 32 AF XY: 0.00337 AC XY: 251 AN XY: 74474

African (AFR) AF: 0.0114 AC: 473 AN: 41558

American (AMR) AF: 0.00255 AC: 39 AN: 15306

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

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

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68010

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.000622 Hom.: 1

Bravo AF: 0.00390

ESP6500AA AF: 0.00459 AC: 20

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00107 AC: 129

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000594

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	1	1	Usher syndrome type 1C (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.0082	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	1.7	L
PhyloP100		7.1
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.19
Sift	Benign	0.045	D
Sift4G	Uncertain	0.020	D
Polyphen		1.0	D
Vest4		0.51
MVP		0.75
MPC		0.37
ClinPred		0.013	T
GERP RS		5.0
Varity_R		0.15
gMVP		0.28
Mutation Taster		=48/52	disease causing

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: rs35336155; hg19: chr11-17544404;