11-17517424-C-T

Variant names:

• chr11-17517424-C-T
• rs115931035
• NM_005709.4:c.1261G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005709.4(USH1C):​c.1261G>A​(p.Gly421Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00307 in 1,593,664 control chromosomes in the GnomAD database, including 137 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 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. G421D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.015 (66 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (71 hom.)
• Consequence: USH1C NM_005709.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.14
• Publications: 4 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026290119).
• BP6: Variant 11-17517424-C-T is Benign according to our data. Variant chr11-17517424-C-T is described in ClinVar as Benign. ClinVar VariationId is 45426.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0519 is higher than 0.05.

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.1261G>A	p.Gly421Ser	missense	Exon 15 of 21	NP_005700.2
	USH1C	NM_153676.4	MANE Select	c.1211-1134G>A		intron	N/A	NP_710142.1
	USH1C	NM_001440679.1		c.1294G>A	p.Gly432Ser	missense	Exon 15 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.1261G>A	p.Gly421Ser	missense	Exon 15 of 21	ENSP00000317018.4
	USH1C	ENST00000527020.5	TSL:1	c.1204G>A	p.Gly402Ser	missense	Exon 14 of 20	ENSP00000436934.1
	USH1C	ENST00000527720.5	TSL:1	c.1168G>A	p.Gly390Ser	missense	Exon 14 of 20	ENSP00000432944.1

Frequencies

GnomAD3 genomes AF: 0.0146 AC: 2225 AN: 152172 Hom.: 66 Cov.: 32

Gnomad AFR AF: 0.0494

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00753

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000367

Gnomad OTH AF: 0.0120

GnomAD2 exomes AF: 0.00397 AC: 869 AN: 219106 AF XY: 0.00318

Gnomad AFR exome AF: 0.0500

Gnomad AMR exome AF: 0.00328

Gnomad ASJ exome AF: 0.00287

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000433

Gnomad OTH exome AF: 0.00449

GnomAD4 exome AF: 0.00184 AC: 2654 AN: 1441374 Hom.: 71 Cov.: 32 AF XY: 0.00165 AC XY: 1177 AN XY: 714746

African (AFR) AF: 0.0539 AC: 1788 AN: 33148

American (AMR) AF: 0.00374 AC: 158 AN: 42280

Ashkenazi Jewish (ASJ) AF: 0.00303 AC: 78 AN: 25710

East Asian (EAS) AF: 0.00 AC: 0 AN: 38924

South Asian (SAS) AF: 0.000121 AC: 10 AN: 82670

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51872

Middle Eastern (MID) AF: 0.00421 AC: 24 AN: 5698

European-Non Finnish (NFE) AF: 0.000310 AC: 342 AN: 1101466

Other (OTH) AF: 0.00426 AC: 254 AN: 59606

GnomAD4 genome AF: 0.0147 AC: 2232 AN: 152290 Hom.: 66 Cov.: 32 AF XY: 0.0147 AC XY: 1095 AN XY: 74466

African (AFR) AF: 0.0494 AC: 2054 AN: 41556

American (AMR) AF: 0.00752 AC: 115 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3472

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

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

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

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000368 AC: 25 AN: 68020

Other (OTH) AF: 0.0118 AC: 25 AN: 2112

Alfa AF: 0.00689 Hom.: 59

Bravo AF: 0.0168

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0423 AC: 186

ESP6500EA AF: 0.000815 AC: 7

ExAC AF: 0.00434 AC: 526

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	21
DANN	Benign	0.46
DEOGEN2	Benign	0.045	T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.68	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N
PhyloP100		1.1
PROVEAN	Benign	0.75	N
REVEL	Benign	0.026
Sift	Benign	0.90	T
Sift4G	Benign	0.47	T
Polyphen		0.0050	B
Vest4		0.14
MVP		0.18
ClinPred		0.0016	T
GERP RS		3.6
Varity_R		0.031
Mutation Taster		=100/0	polymorphism (auto)

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: rs115931035; hg19: chr11-17538971;