NM_173477.5:c.*1900G>C

Variant names:

• chr17-74916173-C-G
• rs1568448
• NM_173477.5:c.*1900G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_173477.5(USH1G):​c.*1900G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.367 in 152,144 control chromosomes in the GnomAD database, including 11,730 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (11710 hom., cov: 31)
  • Exomes 𝑓: 0.49 (20 hom.)
• Consequence: USH1G NM_173477.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.32
• Publications: 6 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 17-74916173-C-G is Benign according to our data. Variant chr17-74916173-C-G is described in ClinVar as [Benign]. Clinvar id is 325030.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.504 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH1G	NM_173477.5	c.*1900G>C		3_prime_UTR_variant	Exon 3 of 3	ENST00000614341.5	NP_775748.2
USH1G	NM_001282489.3	c.*1900G>C		3_prime_UTR_variant	Exon 3 of 3		NP_001269418.1
USH1G	XM_011524296.2	c.*1900G>C		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.*1900G>C		3_prime_UTR_variant	Exon 3 of 3	1	NM_173477.5	ENSP00000480279.1

Frequencies

GnomAD3 genomes AF: 0.367 AC: 55725 AN: 151856 Hom.: 11698 Cov.: 31

Gnomad AFR AF: 0.169

Gnomad AMI AF: 0.582

Gnomad AMR AF: 0.513

Gnomad ASJ AF: 0.273

Gnomad EAS AF: 0.322

Gnomad SAS AF: 0.468

Gnomad FIN AF: 0.481

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.436

Gnomad OTH AF: 0.363

GnomAD4 exome AF: 0.488 AC: 83 AN: 170 Hom.: 20 Cov.: 0 AF XY: 0.447 AC XY: 51 AN XY: 114

African (AFR) AF: 0.00 AC: 0 AN: 4

American (AMR) AF: 0.500 AC: 1 AN: 2

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 2 AN: 2

East Asian (EAS) AF: 0.500 AC: 2 AN: 4

South Asian (SAS) AF: 0.333 AC: 2 AN: 6

European-Finnish (FIN) AF: 0.458 AC: 11 AN: 24

Middle Eastern (MID) AF: 0.333 AC: 2 AN: 6

European-Non Finnish (NFE) AF: 0.519 AC: 55 AN: 106

Other (OTH) AF: 0.500 AC: 8 AN: 16

GnomAD4 genome AF: 0.367 AC: 55754 AN: 151974 Hom.: 11710 Cov.: 31 AF XY: 0.374 AC XY: 27755 AN XY: 74296

African (AFR) AF: 0.168 AC: 6980 AN: 41458

American (AMR) AF: 0.513 AC: 7843 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.273 AC: 947 AN: 3472

East Asian (EAS) AF: 0.323 AC: 1660 AN: 5146

South Asian (SAS) AF: 0.470 AC: 2264 AN: 4820

European-Finnish (FIN) AF: 0.481 AC: 5081 AN: 10570

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.436 AC: 29619 AN: 67918

Other (OTH) AF: 0.362 AC: 763 AN: 2106

Alfa AF: 0.403 Hom.: 1728

Bravo AF: 0.357

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	6.7
DANN	Benign	0.51
PhyloP100		3.3
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: rs1568448; hg19: chr17-72912265;