rs145448362

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr17-74922991-G-A
• chr17-74922991-G-C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BS1_Supporting

The NM_173477.5(USH1G):​c.83C>T​(p.Pro28Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000998 in 1,566,474 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P28P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00060 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0010 (1 hom.)
• Consequence: USH1G NM_173477.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:1
• 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: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.081706524).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000605 (92/152186) while in subpopulation NFE AF = 0.00126 (86/68028). AF 95% confidence interval is 0.00105. There are 0 homozygotes in GnomAd4. There are 40 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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>T	p.Pro28Leu	missense	Exon 1 of 3	NP_775748.2
	USH1G	NM_001282489.3		c.-174C>T		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>T	p.Pro28Leu	missense	Exon 1 of 3	ENSP00000480279.1
	OTOP2	ENST00000580223.2	TSL:1	c.-274G>A		5_prime_UTR	Exon 1 of 5	ENSP00000463837.2
	USH1G	ENST00000579243.1	TSL:2	n.83C>T		non_coding_transcript_exon	Exon 1 of 3	ENSP00000462568.1

Frequencies

GnomAD3 genomes AF: 0.000605 AC: 92 AN: 152186 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00126

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000757 AC: 138 AN: 182298 AF XY: 0.000758

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000364

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00161

Gnomad OTH exome AF: 0.00104

GnomAD4 exome AF: 0.00104 AC: 1472 AN: 1414288 Hom.: 1 Cov.: 31 AF XY: 0.00107 AC XY: 747 AN XY: 698568

African (AFR) AF: 0.0000926 AC: 3 AN: 32408

American (AMR) AF: 0.000260 AC: 10 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: 0.0000200 AC: 1 AN: 49974

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

European-Non Finnish (NFE) AF: 0.00130 AC: 1414 AN: 1086280

Other (OTH) AF: 0.000753 AC: 44 AN: 58452

GnomAD4 genome AF: 0.000605 AC: 92 AN: 152186 Hom.: 0 Cov.: 31 AF XY: 0.000538 AC XY: 40 AN XY: 74334

African (AFR) AF: 0.0000965 AC: 4 AN: 41446

American (AMR) AF: 0.000131 AC: 2 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00126 AC: 86 AN: 68028

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

Alfa AF: 0.00134 Hom.: 4

Bravo AF: 0.000699

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.000419 AC: 50

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	4	1	not provided (5)
-	3	-	Usher syndrome type 1G (3)
-	1	-	not specified (1)
-	1	-	Optic atrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Benign	0.0025	T
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	28
DANN	Uncertain	0.98
DEOGEN2	Benign	0.14	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.082	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		10
PrimateAI	Pathogenic	0.84	D
Sift4G	Benign	0.19	T
Polyphen		0.76	P
Vest4		0.59
MVP		0.50
ClinPred		0.14	T
GERP RS		4.1
PromoterAI		-0.011	Neutral
Varity_R		0.30
gMVP		0.65
Mutation Taster		=13/87	disease causing

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;