NM_173477.5:c.163G>C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_173477.5(USH1G):c.163G>C(p.Gly55Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000287 in 1,392,446 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000029 ( 0 hom. )

Consequence

USH1G
NM_173477.5 missense, splice_region

Scores

Splicing: ADA: 0.4101

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 7.88

Publications

0 publications found

Variant links:

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 links:

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]

OTOP2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.849

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH1G	NM_173477.5 link	c.163G>C	p.Gly55Arg	missense_variant, splice_region_variant	Exon 1 of 3	ENST00000614341.5	NP_775748.2
USH1G	NM_001282489.3 link	c.-94G>C		splice_region_variant	Exon 1 of 3		NP_001269418.1	Q495M9B4DL95
USH1G	NM_001282489.3 link	c.-94G>C		5_prime_UTR_variant	Exon 1 of 3		NP_001269418.1	Q495M9B4DL95
USH1G	XM_011524296.2 link	c.-481G>C		upstream_gene_variant			XP_011522598.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
USH1G	ENST00000614341.5 link	c.163G>C	p.Gly55Arg	missense_variant, splice_region_variant	Exon 1 of 3	1	NM_173477.5	ENSP00000480279.1	Q495M9
USH1G	ENST00000579243.1 link	n.163G>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 1 of 3	2		ENSP00000462568.1	J3KSN5
OTOP2	ENST00000580223.2 link	c.-354C>G		upstream_gene_variant		1		ENSP00000463837.2	A0A6E1ZAN8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000128

AC:

AN:

156070

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000287

AC:

AN:

1392446

Hom.:

Cov.:

AF XY:

0.00000292

AC XY:

AN XY:

685366

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31542

American (AMR)

AF:

0.00

AC:

AN:

35568

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25012

East Asian (EAS)

AF:

0.00

AC:

AN:

35568

South Asian (SAS)

AF:

0.0000507

AC:

AN:

78946

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48656

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5664

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1073804

Other (OTH)

AF:

0.00

AC:

AN:

57686

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Jun 30, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.163G>C (p.G55R) alteration is located in exon 1 (coding exon 1) of the USH1G gene. This alteration results from a G to C substitution at nucleotide position 163, causing the glycine (G) at amino acid position 55 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Apr 03, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available"). This variant has not been reported in the literature in individuals affected with USH1G-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.009%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 55 of the USH1G protein (p.Gly55Arg). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Uncertain

0.068

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.27

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.91

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.85

MetaSVM

Benign

-0.34

MutationAssessor

Uncertain

2.7

PhyloP100

7.9

PrimateAI

Pathogenic

0.91

Sift4G

Uncertain

0.0050

Polyphen

1.0

Vest4

0.74

MutPred

0.77

Gain of solvent accessibility (P = 0.0055);

MVP

0.54

ClinPred

0.91

GERP RS

4.0

PromoterAI

0.016

Neutral

(source)

Varity_R

0.79

gMVP

0.84

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.41

dbscSNV1_RF

Benign

0.61

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over