NM_153676.4:c.307C>A

Variant names:

• chr11-17531234-G-T
• rs397517880
• NM_153676.4:c.307C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP3

The NM_153676.4(USH1C):​c.307C>A​(p.Arg103Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R103C) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: USH1C NM_153676.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.76
• Publications: 0 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 Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Usher syndrome type 1C

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, PanelApp Australia
• autosomal recessive nonsyndromic hearing loss 18A

  Inheritance: AR, Unknown Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_153676.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-17531233-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 39427.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.747

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH1C	NM_153676.4	c.307C>A	p.Arg103Ser	missense_variant	Exon 4 of 27	ENST00000005226.12	NP_710142.1
USH1C	NM_005709.4	c.307C>A	p.Arg103Ser	missense_variant	Exon 4 of 21	ENST00000318024.9	NP_005700.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH1C	ENST00000005226.12	c.307C>A	p.Arg103Ser	missense_variant	Exon 4 of 27	5	NM_153676.4	ENSP00000005226.7
USH1C	ENST00000318024.9	c.307C>A	p.Arg103Ser	missense_variant	Exon 4 of 21	1	NM_005709.4	ENSP00000317018.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461838 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727226

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

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

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53364

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

May 10, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 1058911). This variant has not been reported in the literature in individuals affected with USH1C-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 103 of the USH1C protein (p.Arg103Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Benign	-0.013	T
BayesDel_noAF	Benign	-0.26
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T;.;.;.;T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.93	D;D;D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.75	D;D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.53	N;.;N;N;.
PhyloP100		4.8
PrimateAI	Pathogenic	0.80	D
PROVEAN	Pathogenic	-5.6	D;D;D;D;D
REVEL	Uncertain	0.41
Sift	Uncertain	0.013	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;.
Polyphen		1.0	D;.;D;.;.
Vest4		0.93
MutPred		0.70		Loss of sheet (P = 0.0037);.;Loss of sheet (P = 0.0037);Loss of sheet (P = 0.0037);.;
MVP		0.53
MPC		0.41
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.94
gMVP		0.79
Mutation Taster		=29/71	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs397517880; hg19: chr11-17552781;