chr19-17250414-G-A

Variant names:

• chr19-17250414-G-A
• rs143580327
• NM_031941.4:c.1923C>T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_031941.4(USHBP1):​c.1923C>T​(p.Ser641Ser) 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

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]

ENSG00000269095 (HGNC:):

ACMG classification

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 rank	MANE	Protein	UniProt
USHBP1	NM_031941.4	c.1923C>T	p.Ser641Ser	splice_region_variant, synonymous_variant	Exon 13 of 13	ENST00000252597.8	NP_114147.2
USHBP1	NM_001321417.2	c.1923C>T	p.Ser641Ser	splice_region_variant, synonymous_variant	Exon 13 of 13		NP_001308346.1
USHBP1	NM_001297703.2	c.1731C>T	p.Ser577Ser	splice_region_variant, synonymous_variant	Exon 12 of 12		NP_001284632.1
USHBP1	NR_135632.2	n.2164C>T		splice_region_variant, 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	c.1923C>T	p.Ser641Ser	splice_region_variant, synonymous_variant	Exon 13 of 13	1	NM_031941.4	ENSP00000252597.2
ENSG00000269095	ENST00000594059.1	c.-83+1168C>T		intron_variant	Intron 3 of 4	4		ENSP00000473056.1

Frequencies

GnomAD3 genomes AF: 0.000486 AC: 74 AN: 152216 Hom.: 0 Cov.: 32

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: 99 AN: 247090 Hom.: 0 AF XY: 0.000402 AC XY: 54 AN XY: 134230

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.: 1 Cov.: 33 AF XY: 0.000532 AC XY: 386 AN XY: 725822

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: 74 AN: 152334 Hom.: 0 Cov.: 32 AF XY: 0.000389 AC XY: 29 AN XY: 74484

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.: 0

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

Submissions by phenotype

not specified Benign:1

May 30, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Other links and lift over

dbSNP: rs143580327; hg19: chr19-17361223; COSMIC: COSV99048647; COSMIC: COSV99048647;