chr17-74916891-GCA-G

Variant names:

• chr17-74916891-GCA-G
• rs746904393
• NM_173477.5:c.*1180_*1181delTG

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_173477.5(USH1G):​c.*1180_*1181delTG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0395 in 152,390 control chromosomes in the GnomAD database, including 349 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.040 (349 hom., cov: 33)
  • Exomes 𝑓: 0.011 (0 hom.)
• Consequence: USH1G NM_173477.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.204
• 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 -10 ACMG points.

• BP6: Variant 17-74916891-GCA-G is Benign according to our data. Variant chr17-74916891-GCA-G is described in ClinVar as [Likely_benign]. Clinvar id is 325037.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.133 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH1G	NM_173477.5	c.*1180_*1181delTG		3_prime_UTR_variant	Exon 3 of 3	ENST00000614341.5	NP_775748.2
USH1G	NM_001282489.3	c.*1180_*1181delTG		3_prime_UTR_variant	Exon 3 of 3		NP_001269418.1
USH1G	XM_011524296.2	c.*1180_*1181delTG		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.*1180_*1181delTG		3_prime_UTR_variant	Exon 3 of 3	1	NM_173477.5	ENSP00000480279.1

Frequencies

GnomAD3 genomes AF: 0.0395 AC: 5976 AN: 151456 Hom.: 343 Cov.: 33

Gnomad AFR AF: 0.136

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000416

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0417

Gnomad NFE AF: 0.000546

Gnomad OTH AF: 0.0335

GnomAD4 exome AF: 0.0110 AC: 9 AN: 816 Hom.: 0 AF XY: 0.0100 AC XY: 6 AN XY: 598

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 14

American (AMR) AF: 0.00 AC: 0 AN: 20

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2

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

South Asian (SAS) AF: 0.0286 AC: 2 AN: 70

European-Finnish (FIN) AF: 0.0294 AC: 1 AN: 34

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 6

European-Non Finnish (NFE) AF: 0.00828 AC: 5 AN: 604

Other (OTH) AF: 0.0172 AC: 1 AN: 58

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0396 AC: 6006 AN: 151574 Hom.: 349 Cov.: 33 AF XY: 0.0386 AC XY: 2858 AN XY: 74054

African (AFR) AF: 0.136 AC: 5636 AN: 41312

American (AMR) AF: 0.0163 AC: 248 AN: 15228

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000417 AC: 2 AN: 4800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10520

Middle Eastern (MID) AF: 0.0445 AC: 13 AN: 292

European-Non Finnish (NFE) AF: 0.000546 AC: 37 AN: 67780

Other (OTH) AF: 0.0332 AC: 70 AN: 2110

Alfa AF: 0.0000646 Hom.: 0

Bravo AF: 0.0467

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Retinitis pigmentosa-deafness syndrome Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.20
Mutation Taster		=100/0	polymorphism (auto)

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: rs746904393; hg19: chr17-72912983;