Variant rs377002861 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_153676.4(USH1C):c.1889T>C(p.Leu630Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00003 in 1,466,810 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

USH1C
NM_153676.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.78

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH1C	NM_153676.4 link	c.1889T>C	p.Leu630Pro	missense_variant	18/27	ENST00000005226.12	NP_710142.1	Q9Y6N9-5
USH1C	NM_005709.4 link	c.1285-7500T>C		intron_variant		ENST00000318024.9	NP_005700.2	Q9Y6N9-1A0A0S2Z4U9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH1C	ENST00000005226.12 link	c.1889T>C	p.Leu630Pro	missense_variant	18/27	5	NM_153676.4	ENSP00000005226.7		Q9Y6N9-5
USH1C	ENST00000318024.9 link	c.1285-7500T>C		intron_variant		1	NM_005709.4	ENSP00000317018.4		Q9Y6N9-1

Frequencies

GnomAD3 genomes

AF:

0.000137

AC:

AN:

131562

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000512

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000279

AC:

AN:

251054

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135702

show subpopulations

Gnomad AFR exome

AF:

0.000370

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000195

AC:

AN:

1335248

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

661898

show subpopulations

Gnomad4 AFR exome

AF:

0.000704

Gnomad4 AMR exome

AF:

0.0000245

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.71e-7

Gnomad4 OTH exome

AF:

0.0000577

GnomAD4 genome

AF:

0.000137

AC:

AN:

131562

Hom.:

Cov.:

AF XY:

0.000128

AC XY:

AN XY:

62392

show subpopulations

Gnomad4 AFR

AF:

0.000512

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000161

Hom.:

ESP6500AA

AF:

0.000455

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 16, 2010

Variant classified as Uncertain Significance - Favor Benign. The Leu630Pro varia nt in USH1C has not been reported in the literature nor previously identified by our laboratory. This residue is conserved across species; however, computationa l analyses (PolyPhen, SIFT, AlignGVGD) provide inconsistent predictions regardin g the impact to the protein though this information is not very predictive of pa thogenicity anyway. In summary, the clinical significance of this variant cannot be determined at this time; however based upon the identification of the varian t in a patient with another explanation for hearing loss and without a variant o n the second copy of USH1C, we would lean towards a more likely benign role. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.35

CADD

Uncertain

DANN

Uncertain

1.0

Eigen

Benign

-0.030

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.57

M_CAP

Benign

0.071

MetaRNN

Uncertain

0.45

MetaSVM

Benign

-1.1

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-0.77

REVEL

Benign

0.055

Sift

Pathogenic

0.0

Sift4G

Benign

0.35

Vest4

0.69

MVP

0.45

MPC

0.13

ClinPred

0.70

GERP RS

5.9

gMVP

0.38

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over