19-17251613-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_031941.4(USHBP1):c.1891G>C(p.Glu631Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,613,842 control chromosomes in the GnomAD database, including 1 homozygotes. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E631K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000016 ( 1 hom. )

Consequence

USHBP1
NM_031941.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.11

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 Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.26844627).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
USHBP1	NM_031941.4 linkuse as main transcript	c.1891G>C	p.Glu631Gln	missense_variant	12/13	ENST00000252597.8
USHBP1	NM_001321417.2 linkuse as main transcript	c.1891G>C	p.Glu631Gln	missense_variant	12/13
USHBP1	NM_001297703.2 linkuse as main transcript	c.1699G>C	p.Glu567Gln	missense_variant	11/12
USHBP1	NR_135632.2 linkuse as main transcript	n.2132G>C		non_coding_transcript_exon_variant	13/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USHBP1	ENST00000252597.8 linkuse as main transcript	c.1891G>C	p.Glu631Gln	missense_variant	12/13	1	NM_031941.4	P1	Q8N6Y0-1
USHBP1	ENST00000431146.6 linkuse as main transcript	c.1699G>C	p.Glu567Gln	missense_variant	11/12	2
USHBP1	ENST00000324554.9 linkuse as main transcript	c.*857G>C		3_prime_UTR_variant, NMD_transcript_variant	13/14	2
USHBP1	ENST00000597928.5 linkuse as main transcript	c.*3011G>C		3_prime_UTR_variant, NMD_transcript_variant	11/12	2			Q8N6Y0-2

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152048

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251436

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135900

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000157

AC:

AN:

1461794

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727192

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000198

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152048

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74268

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

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

Oct 16, 2023

The c.1891G>C (p.E631Q) alteration is located in exon 12 (coding exon 11) of the USHBP1 gene. This alteration results from a G to C substitution at nucleotide position 1891, causing the glutamic acid (E) at amino acid position 631 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

0.10

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.46

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Benign

0.052

T;.

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.33

LIST_S2

Benign

0.79

T;T

M_CAP

Benign

0.046

MetaRNN

Benign

0.27

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Uncertain

2.2

M;.

MutationTaster

Benign

0.99

D;N;N

PrimateAI

Benign

0.41

PROVEAN

Benign

-2.3

N;N

REVEL

Benign

0.091

Sift

Uncertain

0.028

D;D

Sift4G

Benign

0.062

T;T

Polyphen

0.99

D;.

Vest4

0.37

MutPred

0.30

Loss of helix (P = 0.0304);.;

MVP

0.50

MPC

0.46

ClinPred

0.56

GERP RS

0.79

Varity_R

0.10

gMVP

0.22

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