17-74923048-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_173477.5(USH1G):c.26C>T(p.Ala9Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000697 in 1,435,352 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: USH1G NM_173477.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.96

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

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.884

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH1G	NM_173477.5	c.26C>T	p.Ala9Val	missense_variant	1/3	ENST00000614341.5
USH1G	NM_001282489.3	c.-231C>T		5_prime_UTR_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH1G	ENST00000614341.5	c.26C>T	p.Ala9Val	missense_variant	1/3	1	NM_173477.5	P1
OTOP2	ENST00000580223.2	c.-231+14G>A		intron_variant		1
USH1G	ENST00000579243.1	c.26C>T	p.Ala9Val	missense_variant, NMD_transcript_variant	1/3	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.97e-7 AC: 1 AN: 1435352 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 710836

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.11e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 07, 2023

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 9 of the USH1G protein (p.Ala9Val). This variant is not present in population databases (gnomAD no frequency). 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt USH1G protein function. ClinVar contains an entry for this variant (Variation ID: 1008908). This variant has not been reported in the literature in individuals affected with USH1G-related conditions. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
Cadd	Pathogenic	33
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.43	T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.030	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Benign	-0.56	T
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.85	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.69		Loss of disorder (P = 0.0276);
MVP		0.52
ClinPred		0.98	D
GERP RS		4.1
Varity_R		0.62
gMVP		0.78

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: rs1322425552; hg19: chr17-72919143;