rs34077456

chr11-17501084-C-Achr11-17501084-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.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. 11/19 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. 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:3
• Conservation: PhyloP100: 2.68

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=0.0063123703).
• BP6: Variant 11-17501084-C-A is Benign according to our data. Variant chr11-17501084-C-A is described in ClinVar as [Benign]. Clinvar id is 47999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-17501084-C-A is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 39 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH1C	NM_153676.4	c.2347G>T	p.Ala783Ser	missense_variant	23/27	ENST00000005226.12
USH1C	NM_005709.4	c.1447G>T	p.Ala483Ser	missense_variant	18/21	ENST00000318024.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH1C	ENST00000005226.12	c.2347G>T	p.Ala783Ser	missense_variant	23/27	5	NM_153676.4
USH1C	ENST00000318024.9	c.1447G>T	p.Ala483Ser	missense_variant	18/21	1	NM_005709.4	P1

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

GnomAD3 exomes AF: 0.00316 AC: 794 AN: 250894 Hom.: 14 AF XY: 0.00228 AC XY: 309 AN XY: 135678

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 SAS exome AF: 0.0000654

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

Gnomad4 AFR exome AF: 0.0436

Gnomad4 AMR exome AF: 0.00217

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000594

Gnomad4 OTH exome AF: 0.00275

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

Gnomad4 AFR AF: 0.0425

Gnomad4 AMR AF: 0.00346

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.00199 Hom.: 2

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

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 23, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 04, 2011	Ala783Ser in exon 23 of USH1C: This variant is not expected to have clinical sig nificance because it was identified in dbSNP in 2.6% (5/194) control chromosomes (rs34077456). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

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;D;D;D
MetaRNN	Benign	0.0063	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.080	N;.;.;.
MutationTaster	Benign	0.50	D;D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.44	N;N;N;N
REVEL	Benign	0.041
Sift	Benign	0.47	T;T;T;T
Sift4G	Benign	0.54	T;T;T;T
Polyphen		0.0	B;.;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs34077456; hg19: chr11-17522631; COSMIC: COSV99040696; COSMIC: COSV99040696;