Genetic Variant USHBP1:p.Ser551Arg (chr19-17255424-G-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_031941.4(USHBP1):c.1653C>A(p.Ser551Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000131 in 1,613,958 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 2 hom. )

Consequence

USHBP1
NM_031941.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0770

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 -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.10559878).

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USHBP1	NM_031941.4 link	c.1653C>A	p.Ser551Arg	missense_variant	Exon 10 of 13	ENST00000252597.8	NP_114147.2	Q8N6Y0-1A0A024R7H3
USHBP1	NM_001321417.2 link	c.1653C>A	p.Ser551Arg	missense_variant	Exon 10 of 13		NP_001308346.1	Q8N6Y0-1A0A024R7H3
USHBP1	NM_001297703.2 link	c.1461C>A	p.Ser487Arg	missense_variant	Exon 9 of 12		NP_001284632.1	Q8N6Y0G8JLM4B4DUE8
USHBP1	NR_135632.2 link	n.1894C>A		non_coding_transcript_exon_variant	Exon 11 of 14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USHBP1	ENST00000252597.8 link	c.1653C>A	p.Ser551Arg	missense_variant	Exon 10 of 13	1	NM_031941.4	ENSP00000252597.2		Q8N6Y0-1
ENSG00000269095	ENST00000594059.1 link	c.-352C>A		5_prime_UTR_variant	Exon 1 of 5	4		ENSP00000473056.1		M0R384

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000116

AC:

AN:

250936

Hom.:

AF XY:

0.0000958

AC XY:

AN XY:

135696

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000185

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000137

AC:

200

AN:

1461828

Hom.:

Cov.:

AF XY:

0.000146

AC XY:

106

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000164

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000789

AC:

AN:

152130

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.000117

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 23, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1653C>A (p.S551R) alteration is located in exon 10 (coding exon 9) of the USHBP1 gene. This alteration results from a C to A substitution at nucleotide position 1653, causing the serine (S) at amino acid position 551 to be replaced by an arginine (R). 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

Pathogenic

0.61

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.014

T;.

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.055

LIST_S2

Benign

0.78

T;T

M_CAP

Benign

0.029

MetaRNN

Benign

0.11

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Uncertain

2.0

M;.

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.87

N;N

REVEL

Benign

0.13

Sift

Benign

0.094

T;T

Sift4G

Benign

0.095

T;T

Polyphen

1.0

D;.

Vest4

0.30

MutPred

0.23

Loss of glycosylation at S551 (P = 0.0011);.;

MVP

0.31

MPC

0.67

ClinPred

0.14

GERP RS

0.011

Varity_R

0.055

gMVP

0.37

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

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