rs142751309

chr11-17498164-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_153676.4(USH1C):c.2488G>A(p.Gly830Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000784 in 1,613,860 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G830E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0040 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00044 (4 hom.)
• Consequence: USH1C NM_153676.4 missense, splice_region
• Scores: Splicing: ADA: 0.03882
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.30

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009979993).
• BP6: Variant 11-17498164-C-T is Benign according to our data. Variant chr11-17498164-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 48005.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-17498164-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00404 (616/152288) while in subpopulation AFR AF= 0.0141 (584/41552). AF 95% confidence interval is 0.0131. There are 2 homozygotes in gnomad4. There are 274 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH1C	NM_153676.4	c.2488G>A	p.Gly830Arg	missense_variant, splice_region_variant	24/27	ENST00000005226.12
USH1C	NM_005709.4	c.1588G>A	p.Gly530Arg	missense_variant, splice_region_variant	19/21	ENST00000318024.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH1C	ENST00000005226.12	c.2488G>A	p.Gly830Arg	missense_variant, splice_region_variant	24/27	5	NM_153676.4
USH1C	ENST00000318024.9	c.1588G>A	p.Gly530Arg	missense_variant, splice_region_variant	19/21	1	NM_005709.4	P1

Frequencies

GnomAD3 genomes AF: 0.00404 AC: 615 AN: 152170 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.0141

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00117 AC: 293 AN: 251252 Hom.: 1 AF XY: 0.000972 AC XY: 132 AN XY: 135792

Gnomad AFR exome AF: 0.0156

Gnomad AMR exome AF: 0.000665

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000704

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000444 AC: 649 AN: 1461572 Hom.: 4 Cov.: 30 AF XY: 0.000414 AC XY: 301 AN XY: 727120

Gnomad4 AFR exome AF: 0.0146

Gnomad4 AMR exome AF: 0.000783

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000928

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000513

Gnomad4 OTH exome AF: 0.000894

GnomAD4 genome AF: 0.00404 AC: 616 AN: 152288 Hom.: 2 Cov.: 33 AF XY: 0.00368 AC XY: 274 AN XY: 74458

Gnomad4 AFR AF: 0.0141

Gnomad4 AMR AF: 0.000981

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00199 Hom.: 0

Bravo AF: 0.00468

ESP6500AA AF: 0.0141 AC: 62

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00141 AC: 171

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 19, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 15, 2012

Gly830Arg in Exon 24 of USH1C: This variant is not expected to have clinical sig nificance because it has been identified in 1.3% (47/3738) of African American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs142751309). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.31
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.36	T;.;.;.
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.96	D;D;D;D
MetaRNN	Benign	0.010	T;T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Uncertain	2.1	M;.;.;.
MutationTaster	Benign	0.99	D;D;D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-2.1	N;N;D;N
REVEL	Benign	0.22
Sift	Uncertain	0.0030	D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D
Polyphen		1.0	D;.;D;.
Vest4		0.58
MutPred		0.63		Gain of sheet (P = 0.0149);.;.;.;
MVP		0.66
MPC		0.16
ClinPred		0.011	T
GERP RS		3.5
Varity_R		0.30
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.039
dbscSNV1_RF	Benign	0.28
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

Publications

LitVar

Other links and lift over

dbSNP: rs142751309; hg19: chr11-17519711; COSMIC: COSV50015469; COSMIC: COSV50015469;