rs769903865

Variant names:

• chr17-74923081-G-A
• rs769903865
• NM_173477.5:c.-8C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-74923081-G-A
• chr17-74923081-G-C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_173477.5(USH1G):​c.-8C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000308 in 1,577,150 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00032 (0 hom.)
• Consequence: USH1G NM_173477.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.98
• 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]

OTOP2 (HGNC:19657): (otopetrin 2) Predicted to enable proton channel activity. Predicted to be involved in proton transmembrane transport. Predicted to be located in plasma membrane. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173477.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH1G	NM_173477.5	MANE Select	c.-8C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 3	NP_775748.2
	USH1G	NM_173477.5	MANE Select	c.-8C>T		5_prime_UTR	Exon 1 of 3	NP_775748.2
	USH1G	NM_001282489.3		c.-264C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 3	NP_001269418.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH1G	ENST00000614341.5	TSL:1 MANE Select	c.-8C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 3	ENSP00000480279.1
	USH1G	ENST00000614341.5	TSL:1 MANE Select	c.-8C>T		5_prime_UTR	Exon 1 of 3	ENSP00000480279.1
	OTOP2	ENST00000580223.2	TSL:1	c.-231+47G>A		intron	N/A	ENSP00000463837.2

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152186 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000249 AC: 51 AN: 205154 AF XY: 0.000270

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00303

Gnomad EAS exome AF: 0.0000626

Gnomad FIN exome AF: 0.0000570

Gnomad NFE exome AF: 0.000236

Gnomad OTH exome AF: 0.000194

GnomAD4 exome AF: 0.000318 AC: 453 AN: 1424964 Hom.: 0 Cov.: 31 AF XY: 0.000332 AC XY: 234 AN XY: 704118

African (AFR) AF: 0.0000305 AC: 1 AN: 32816

American (AMR) AF: 0.0000483 AC: 2 AN: 41382

Ashkenazi Jewish (ASJ) AF: 0.00253 AC: 64 AN: 25344

East Asian (EAS) AF: 0.000105 AC: 4 AN: 38236

South Asian (SAS) AF: 0.00 AC: 0 AN: 82158

European-Finnish (FIN) AF: 0.0000592 AC: 3 AN: 50638

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4332

European-Non Finnish (NFE) AF: 0.000336 AC: 367 AN: 1091478

Other (OTH) AF: 0.000205 AC: 12 AN: 58580

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152186 Hom.: 0 Cov.: 30 AF XY: 0.000256 AC XY: 19 AN XY: 74342

African (AFR) AF: 0.000121 AC: 5 AN: 41462

American (AMR) AF: 0.0000654 AC: 1 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 13 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000444 Hom.: 0

Bravo AF: 0.000208

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)
-	1	-	Usher syndrome type 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	16
DANN	Benign	0.87
PhyloP100		3.0
PromoterAI		-0.046	Neutral

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: rs769903865; hg19: chr17-72919176;