dbSNP rs147601359: USHBP1:p.Arg648Gln (chr19-17250394-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_031941.4(USHBP1):c.1943G>A(p.Arg648Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000806 in 1,613,094 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000060 ( 0 hom. )

Consequence

USHBP1
NM_031941.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.662

Variant links:

Genes affected

USHBP1 (HGNC:24058): (USH1 protein network component harmonin binding protein 1) Enables PDZ domain binding activity. [provided by Alliance of Genome Resources, Apr 2022]

USHBP1 links:

ENSG00000269095 (HGNC:):

ENSG00000269095 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.025895715).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USHBP1	NM_031941.4 link	c.1943G>A	p.Arg648Gln	missense_variant	Exon 13 of 13	ENST00000252597.8	NP_114147.2	Q8N6Y0-1A0A024R7H3
USHBP1	NM_001321417.2 link	c.1943G>A	p.Arg648Gln	missense_variant	Exon 13 of 13		NP_001308346.1	Q8N6Y0-1A0A024R7H3
USHBP1	NM_001297703.2 link	c.1751G>A	p.Arg584Gln	missense_variant	Exon 12 of 12		NP_001284632.1	Q8N6Y0G8JLM4B4DUE8
USHBP1	NR_135632.2 link	n.2184G>A		non_coding_transcript_exon_variant	Exon 14 of 14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USHBP1	ENST00000252597.8 link	c.1943G>A	p.Arg648Gln	missense_variant	Exon 13 of 13	1	NM_031941.4	ENSP00000252597.2		Q8N6Y0-1
ENSG00000269095	ENST00000594059.1 link	c.-83+1188G>A		intron_variant	Intron 3 of 4	4		ENSP00000473056.1		M0R384

Frequencies

GnomAD3 genomes

AF:

0.000283

AC:

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000942

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000999

AC:

AN:

250158

Hom.:

AF XY:

0.0000590

AC XY:

AN XY:

135518

show subpopulations

Gnomad AFR exome

AF:

0.00112

Gnomad AMR exome

AF:

0.0000580

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000354

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000595

AC:

AN:

1460974

Hom.:

Cov.:

AF XY:

0.0000495

AC XY:

AN XY:

726840

show subpopulations

Gnomad4 AFR exome

AF:

0.000926

Gnomad4 AMR exome

AF:

0.0000448

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000414

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.000283

AC:

AN:

152120

Hom.:

Cov.:

AF XY:

0.000256

AC XY:

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.000942

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.000412

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000148

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1943G>A (p.R648Q) alteration is located in exon 13 (coding exon 12) of the USHBP1 gene. This alteration results from a G to A substitution at nucleotide position 1943, causing the arginine (R) at amino acid position 648 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.033

T;.

Eigen

Benign

0.084

Eigen_PC

Benign

0.11

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.78

T;T

M_CAP

Benign

0.0063

MetaRNN

Benign

0.026

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

M;.

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.82

N;N

REVEL

Benign

0.087

Sift

Benign

0.13

T;T

Sift4G

Uncertain

0.037

D;D

Polyphen

0.96

D;.

Vest4

0.13

MVP

0.25

MPC

0.19

ClinPred

0.035

GERP RS

3.5

Varity_R

0.13

gMVP

0.21

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over