19-17250414-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM2BP4_StrongBP6_ModerateBP7

The NM_031941.4(USHBP1):c.1923C>T(p.Ser641=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000542 in 1,610,950 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00049 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00055 ( 1 hom. )

Consequence

USHBP1
NM_031941.4 splice_region, synonymous

Scores

Splicing: ADA: 0.00004424

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -2.72

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 -5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BP6

Variant 19-17250414-G-A is Benign according to our data. Variant chr19-17250414-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2568580.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-2.72 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
USHBP1	NM_031941.4 linkuse as main transcript	c.1923C>T	p.Ser641=	splice_region_variant, synonymous_variant	13/13	ENST00000252597.8
USHBP1	NM_001321417.2 linkuse as main transcript	c.1923C>T	p.Ser641=	splice_region_variant, synonymous_variant	13/13
USHBP1	NM_001297703.2 linkuse as main transcript	c.1731C>T	p.Ser577=	splice_region_variant, synonymous_variant	12/12
USHBP1	NR_135632.2 linkuse as main transcript	n.2164C>T		splice_region_variant, 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.1923C>T	p.Ser641=	splice_region_variant, synonymous_variant	13/13	1	NM_031941.4	P1	Q8N6Y0-1
USHBP1	ENST00000431146.6 linkuse as main transcript	c.1731C>T	p.Ser577=	splice_region_variant, synonymous_variant	12/12	2
USHBP1	ENST00000324554.9 linkuse as main transcript	c.*889C>T		splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant	14/14	2
USHBP1	ENST00000597928.5 linkuse as main transcript	c.*3043C>T		splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant	12/12	2			Q8N6Y0-2

Frequencies

GnomAD3 genomes

AF:

0.000486

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

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:

0.00316

Gnomad NFE

AF:

0.000955

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000401

AC:

AN:

247090

Hom.:

AF XY:

0.000402

AC XY:

AN XY:

134230

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000593

Gnomad ASJ exome

AF:

0.000302

Gnomad EAS exome

AF:

0.0000550

Gnomad SAS exome

AF:

0.0000329

Gnomad FIN exome

AF:

0.000145

Gnomad NFE exome

AF:

0.000794

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000548

AC:

799

AN:

1458616

Hom.:

Cov.:

AF XY:

0.000532

AC XY:

386

AN XY:

725822

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.0000908

Gnomad4 ASJ exome

AF:

0.0000767

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.000135

Gnomad4 NFE exome

AF:

0.000689

Gnomad4 OTH exome

AF:

0.000249

GnomAD4 genome

AF:

0.000486

AC:

AN:

152334

Hom.:

Cov.:

AF XY:

0.000389

AC XY:

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.000144

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:

0.000955

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000509

Hom.:

Bravo

AF:

0.000408

EpiCase

AF:

0.000818

EpiControl

AF:

0.00107

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 30, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

Cadd

Benign

0.087

Dann

Benign

0.80

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000044

dbscSNV1_RF

Benign

0.044

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