19-17250254-G-T

Variant names:

• chr19-17250254-G-T
• rs199788991
• NM_031941.4:c.2083C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_031941.4(USHBP1):​c.2083C>A​(p.Pro695Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,612,708 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. P695L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: USHBP1 NM_031941.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.374
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03728044).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USHBP1	NM_031941.4	c.2083C>A	p.Pro695Thr	missense_variant	Exon 13 of 13	ENST00000252597.8	NP_114147.2
USHBP1	NM_001321417.2	c.2083C>A	p.Pro695Thr	missense_variant	Exon 13 of 13		NP_001308346.1
USHBP1	NM_001297703.2	c.1891C>A	p.Pro631Thr	missense_variant	Exon 12 of 12		NP_001284632.1
USHBP1	NR_135632.2	n.2324C>A		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.2083C>A	p.Pro695Thr	missense_variant	Exon 13 of 13	1	NM_031941.4	ENSP00000252597.2
ENSG00000269095	ENST00000594059.1	c.-83+1328C>A		intron_variant	Intron 3 of 4	4		ENSP00000473056.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152230 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000162 AC: 4 AN: 247004 AF XY: 0.00000745

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000220

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460360 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726456

African (AFR) AF: 0.00 AC: 0 AN: 33446

American (AMR) AF: 0.00 AC: 0 AN: 44540

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26090

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39632

South Asian (SAS) AF: 0.00 AC: 0 AN: 86144

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52866

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5722

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111594

Other (OTH) AF: 0.00 AC: 0 AN: 60326

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152348 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74500

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41586

American (AMR) AF: 0.00 AC: 0 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2108

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 17, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2083C>A (p.P695T) alteration is located in exon 13 (coding exon 12) of the USHBP1 gene. This alteration results from a C to A substitution at nucleotide position 2083, causing the proline (P) at amino acid position 695 to be replaced by a threonine (T). 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	0.081
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Benign	0.0075	T;.
Eigen	Benign	-0.97
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.57	T;T
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.037	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L;.
PhyloP100		0.37
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.0090
Sift	Benign	0.043	D;D
Sift4G	Benign	0.21	T;T
Polyphen		0.010	B;.
Vest4		0.18
MVP		0.085
MPC		0.68
ClinPred		0.052	T
GERP RS		2.3
Varity_R		0.044
gMVP		0.33
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs199788991; hg19: chr19-17361063;