rs201104489

Positions:

• chr11-17509772-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The ENST00000318024.9(USH1C):​c.1284+7629G>A variant causes a intron change. The variant allele was found at a frequency of 0.000044 in 1,592,050 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000062 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000042 (0 hom.)
• Consequence: USH1C ENST00000318024.9 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 3.61

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12764347).
• BP6: Variant 11-17509772-C-T is Benign according to our data. Variant chr11-17509772-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 166382.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH1C	NM_153676.4	c.1597G>A	p.Ala533Thr	missense_variant	18/27	ENST00000005226.12	NP_710142.1
USH1C	NM_005709.4	c.1284+7629G>A		intron_variant		ENST00000318024.9	NP_005700.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH1C	ENST00000005226.12	c.1597G>A	p.Ala533Thr	missense_variant	18/27	5	NM_153676.4	ENSP00000005226
USH1C	ENST00000318024.9	c.1284+7629G>A		intron_variant		1	NM_005709.4	ENSP00000317018	P1

Frequencies

GnomAD3 genomes AF: 0.0000625 AC: 9 AN: 143958 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.0000264

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000421

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000226

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000150

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000668 AC: 16 AN: 239666 Hom.: 0 AF XY: 0.0000459 AC XY: 6 AN XY: 130618

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000553

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000357

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000421 AC: 61 AN: 1448000 Hom.: 0 Cov.: 40 AF XY: 0.0000305 AC XY: 22 AN XY: 720612

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000269

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000324

Gnomad4 OTH exome AF: 0.0000997

GnomAD4 genome AF: 0.0000625 AC: 9 AN: 144050 Hom.: 0 Cov.: 29 AF XY: 0.0000573 AC XY: 4 AN XY: 69852

Gnomad4 AFR AF: 0.0000264

Gnomad4 AMR AF: 0.000420

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000226

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000150

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000959 Hom.: 0

ExAC AF: 0.0000577 AC: 7

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 01, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 27, 2021	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 07, 2014

Variant classified as Uncertain Significance - Favor Benign. The p.Ala533Thr var iant in USH1C has not been previously reported in individuals with hearing loss, but has been identified in 0.8% (1/128) of Mexican ancestry chromosomes by the 1000 Genomes Project (dbSNP rs201104489). The Alanine (Ala) at position 533 is c onserved in mammals, but at least one mammal (orangutan) is reported to carry a Threonine (Thr) at this position, raising the possibility that this change may b e tolerated. Additional computational prediction tools do not provide strong sup port for or against an impact to the protein. In summary, while the clinical sig nificance of the p.Ala533Thr variant is uncertain, these data suggest that it is more likely to be benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	23
DANN	Uncertain	1.0
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.63	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.90	T
MutationTaster	Benign	1.0	D;D;D;N
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.96	N
REVEL	Benign	0.069
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.27	T
Vest4		0.30
MVP		0.65
MPC		0.28
ClinPred		0.79	D
GERP RS		4.7
gMVP		0.41

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: rs201104489; hg19: chr11-17531319;