17-74922991-G-C

Variant names:

• chr17-74922991-G-C
• rs145448362
• NM_173477.5:c.83C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_173477.5(USH1G):​c.83C>G​(p.Pro28Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000283 in 1,414,292 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P28L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: USH1G NM_173477.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.99
• Publications: 5 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH1G	NM_173477.5	MANE Select	c.83C>G	p.Pro28Arg	missense	Exon 1 of 3	NP_775748.2
	USH1G	NM_001282489.3		c.-174C>G		5_prime_UTR	Exon 1 of 3	NP_001269418.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH1G	ENST00000614341.5	TSL:1 MANE Select	c.83C>G	p.Pro28Arg	missense	Exon 1 of 3	ENSP00000480279.1
	OTOP2	ENST00000580223.2	TSL:1	c.-274G>C		5_prime_UTR	Exon 1 of 5	ENSP00000463837.2
	USH1G	ENST00000579243.1	TSL:2	n.83C>G		non_coding_transcript_exon	Exon 1 of 3	ENSP00000462568.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00 AC: 0 AN: 182298 AF XY: 0.00

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: 0.00000283 AC: 4 AN: 1414292 Hom.: 0 Cov.: 31 AF XY: 0.00000143 AC XY: 1 AN XY: 698572

African (AFR) AF: 0.00 AC: 0 AN: 32408

American (AMR) AF: 0.00 AC: 0 AN: 38390

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25334

East Asian (EAS) AF: 0.00 AC: 0 AN: 37132

South Asian (SAS) AF: 0.00 AC: 0 AN: 80704

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49974

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5614

European-Non Finnish (NFE) AF: 0.00000368 AC: 4 AN: 1086284

Other (OTH) AF: 0.00 AC: 0 AN: 58452

GnomAD4 genome Cov.: 31

ExAC AF: 0.0000168 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	32
DANN	Benign	0.96
DEOGEN2	Benign	0.044	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.033	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
PhyloP100		10
PrimateAI	Pathogenic	0.83	D
Sift4G	Benign	0.33	T
Polyphen		0.99	D
Vest4		0.67
MutPred		0.30		Loss of stability (P = 0.0408)
MVP		0.51
ClinPred		0.96	D
GERP RS		4.1
PromoterAI		-0.0092	Neutral
Varity_R		0.39
gMVP		0.62

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: rs145448362; hg19: chr17-72919086;