chr17-74916961-G-A

Variant names:

• chr17-74916961-G-A
• rs114353953
• NM_173477.5:c.*1112C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_173477.5(USH1G):​c.*1112C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0179 in 150,610 control chromosomes in the GnomAD database, including 79 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.018 (79 hom., cov: 34)
  • Exomes 𝑓: 0.0011 (0 hom.)
• Consequence: USH1G NM_173477.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.18
• Publications: 0 publications found

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]

USH1G Gene-Disease associations (from GenCC):

• Usher syndrome type 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Usher syndrome type 1G

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

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 17-74916961-G-A is Benign according to our data. Variant chr17-74916961-G-A is described in ClinVar as [Benign]. Clinvar id is 890034.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0609 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH1G	NM_173477.5	c.*1112C>T		3_prime_UTR_variant	Exon 3 of 3	ENST00000614341.5	NP_775748.2
USH1G	NM_001282489.3	c.*1112C>T		3_prime_UTR_variant	Exon 3 of 3		NP_001269418.1
USH1G	XM_011524296.2	c.*1112C>T		3_prime_UTR_variant	Exon 3 of 3		XP_011522598.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH1G	ENST00000614341.5	c.*1112C>T		3_prime_UTR_variant	Exon 3 of 3	1	NM_173477.5	ENSP00000480279.1

Frequencies

GnomAD3 genomes AF: 0.0180 AC: 2690 AN: 149566 Hom.: 78 Cov.: 34

Gnomad AFR AF: 0.0630

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00640

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000596

Gnomad SAS AF: 0.000431

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.000356

Gnomad OTH AF: 0.00787

GnomAD4 exome AF: 0.00108 AC: 1 AN: 924 Hom.: 0 Cov.: 0 AF XY: 0.00152 AC XY: 1 AN XY: 656

African (AFR) AF: 0.00 AC: 0 AN: 18

American (AMR) AF: 0.00 AC: 0 AN: 30

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8

East Asian (EAS) AF: 0.00 AC: 0 AN: 8

South Asian (SAS) AF: 0.00 AC: 0 AN: 74

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 58

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 10

European-Non Finnish (NFE) AF: 0.00153 AC: 1 AN: 652

Other (OTH) AF: 0.00 AC: 0 AN: 66

GnomAD4 genome AF: 0.0180 AC: 2693 AN: 149686 Hom.: 79 Cov.: 34 AF XY: 0.0172 AC XY: 1255 AN XY: 72976

African (AFR) AF: 0.0629 AC: 2550 AN: 40538

American (AMR) AF: 0.00639 AC: 96 AN: 15028

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3454

East Asian (EAS) AF: 0.000598 AC: 3 AN: 5018

South Asian (SAS) AF: 0.000431 AC: 2 AN: 4636

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10272

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.000356 AC: 24 AN: 67486

Other (OTH) AF: 0.00779 AC: 16 AN: 2054

Alfa AF: 0.000284 Hom.: 0

Bravo AF: 0.0202

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Usher syndrome type 1G Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.98
DANN	Benign	0.48
PhyloP100		-1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs114353953; hg19: chr17-72913053;