17-74916911-GCA-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BS1_Supporting

The NM_173477.5(USH1G):c.*1160_*1161del variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000906 in 152,362 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00087 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0062 (0 hom.)
• Consequence: USH1G NM_173477.5 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.691

Genes affected

USH1G (HGNC:16356): (USH1 protein network component sans) This gene encodes a protein that contains three ankyrin domains, a class I PDZ-binding motif and a sterile alpha motif. The encoded protein interacts with harmonin, which is associated with Usher syndrome type 1C. This protein plays a role in the development and maintenance of the auditory and visual systems and functions in the cohesion of hair bundles formed by inner ear sensory cells. Mutations in this gene are associated with Usher syndrome type 1G (USH1G). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000872 (132/151390) while in subpopulation AFR AF= 0.00204 (84/41240). AF 95% confidence interval is 0.00169. There are 0 homozygotes in gnomad4. There are 64 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH1G	NM_173477.5	c.*1160_*1161del		3_prime_UTR_variant	3/3	ENST00000614341.5
USH1G	NM_001282489.3	c.*1160_*1161del		3_prime_UTR_variant	3/3
USH1G	XM_011524296.2	c.*1160_*1161del		3_prime_UTR_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH1G	ENST00000614341.5	c.*1160_*1161del		3_prime_UTR_variant	3/3	1	NM_173477.5	P1

Frequencies

GnomAD3 genomes AF: 0.000866 AC: 131 AN: 151272 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00202

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000263

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00105

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000369

Gnomad OTH AF: 0.00145

GnomAD4 exome AF: 0.00617 AC: 6 AN: 972 Hom.: 0 AF XY: 0.00421 AC XY: 3 AN XY: 712

Gnomad4 AFR exome AF: 0.0556

Gnomad4 AMR exome AF: 0.00

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: 0.00575

Gnomad4 OTH exome AF: 0.0172

GnomAD4 genome AF: 0.000872 AC: 132 AN: 151390 Hom.: 0 Cov.: 34 AF XY: 0.000865 AC XY: 64 AN XY: 73974

Gnomad4 AFR AF: 0.00204

Gnomad4 AMR AF: 0.000263

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00105

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.000369

Gnomad4 OTH AF: 0.00143

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Retinitis pigmentosa-deafness syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs368387485; hg19: chr17-72913003;