19-17250280-A-G

Variant summary

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

The NM_031941.4(USHBP1):c.2057T>C(p.Leu686Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000868 in 1,613,580 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L686Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

USHBP1
NM_031941.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.58

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:

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=0.055906057).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
USHBP1	NM_031941.4 linkuse as main transcript	c.2057T>C	p.Leu686Pro	missense_variant	13/13	ENST00000252597.8
USHBP1	NM_001321417.2 linkuse as main transcript	c.2057T>C	p.Leu686Pro	missense_variant	13/13
USHBP1	NM_001297703.2 linkuse as main transcript	c.1865T>C	p.Leu622Pro	missense_variant	12/12
USHBP1	NR_135632.2 linkuse as main transcript	n.2298T>C		non_coding_transcript_exon_variant	14/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USHBP1	ENST00000252597.8 linkuse as main transcript	c.2057T>C	p.Leu686Pro	missense_variant	13/13	1	NM_031941.4	P1	Q8N6Y0-1
USHBP1	ENST00000431146.6 linkuse as main transcript	c.1865T>C	p.Leu622Pro	missense_variant	12/12	2
USHBP1	ENST00000324554.9 linkuse as main transcript	c.*1023T>C		3_prime_UTR_variant, NMD_transcript_variant	14/14	2
USHBP1	ENST00000597928.5 linkuse as main transcript	c.*3177T>C		3_prime_UTR_variant, NMD_transcript_variant	12/12	2			Q8N6Y0-2

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00116

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000360

AC:

AN:

249864

Hom.:

AF XY:

0.0000517

AC XY:

AN XY:

135418

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000490

Gnomad SAS 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:

0.00000479

AC:

AN:

1461296

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

726946

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152284

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00116

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000302

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 29, 2023

The c.2057T>C (p.L686P) alteration is located in exon 13 (coding exon 12) of the USHBP1 gene. This alteration results from a T to C substitution at nucleotide position 2057, causing the leucine (L) at amino acid position 686 to be replaced by a proline (P). 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

0.17

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.16

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Benign

0.22

T;.

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.065

LIST_S2

Benign

0.66

T;T

M_CAP

Benign

0.034

MetaRNN

Benign

0.056

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Uncertain

2.3

M;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.41

PROVEAN

Pathogenic

-4.5

D;D

REVEL

Benign

0.16

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.049

D;T

Polyphen

0.24

B;.

Vest4

0.41

MutPred

0.29

Gain of relative solvent accessibility (P = 0.0023);.;

MVP

0.38

MPC

0.76

ClinPred

0.75

GERP RS

3.5

Varity_R

0.60

gMVP

0.50

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