rs149002004

Positions:

• chr17-74920131-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_173477.5(USH1G):​c.705G>A​(p.Glu235Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,602,758 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00075 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (2 hom.)
• Consequence: USH1G NM_173477.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.95

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 Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 17-74920131-C-T is Benign according to our data. Variant chr17-74920131-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 48136.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-74920131-C-T is described in Lovd as [Likely_benign]. Variant chr17-74920131-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.95 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000755 (115/152390) while in subpopulation NFE AF= 0.0014 (95/68040). AF 95% confidence interval is 0.00117. There are 0 homozygotes in gnomad4. There are 42 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH1G	NM_173477.5	c.705G>A	p.Glu235Glu	synonymous_variant	2/3	ENST00000614341.5	NP_775748.2
USH1G	NM_001282489.3	c.396G>A	p.Glu132Glu	synonymous_variant	2/3		NP_001269418.1
USH1G	XM_011524296.2	c.396G>A	p.Glu132Glu	synonymous_variant	2/3		XP_011522598.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH1G	ENST00000614341.5	c.705G>A	p.Glu235Glu	synonymous_variant	2/3	1	NM_173477.5	ENSP00000480279.1
USH1G	ENST00000579243.1	n.*304G>A		non_coding_transcript_exon_variant	2/3	2		ENSP00000462568.1
USH1G	ENST00000579243.1	n.*304G>A		3_prime_UTR_variant	2/3	2		ENSP00000462568.1

Frequencies

GnomAD3 genomes AF: 0.000755 AC: 115 AN: 152272 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000313

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00140

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000591 AC: 142 AN: 240400 Hom.: 0 AF XY: 0.000608 AC XY: 80 AN XY: 131474

Gnomad AFR exome AF: 0.000128

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00120

Gnomad OTH exome AF: 0.000332

GnomAD4 exome AF: 0.00112 AC: 1620 AN: 1450368 Hom.: 2 Cov.: 42 AF XY: 0.00104 AC XY: 753 AN XY: 722050

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000236

Gnomad4 NFE exome AF: 0.00140

Gnomad4 OTH exome AF: 0.000862

GnomAD4 genome AF: 0.000755 AC: 115 AN: 152390 Hom.: 0 Cov.: 32 AF XY: 0.000564 AC XY: 42 AN XY: 74522

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00140

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00100 Hom.: 0

Bravo AF: 0.000763

EpiCase AF: 0.00136

EpiControl AF: 0.00101

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 21, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 21, 2016	p.Glu235Glu in exon 2 of USH1G: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located ne ar a splice junction. This variant has been identified in 58/64382 of European c hromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute .org; dbSNP rs149002004). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	13
DANN	Benign	0.88

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: rs149002004; hg19: chr17-72916226;