19-17251938-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_031941.4(USHBP1):c.1772C>T(p.Ala591Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000717 in 1,394,670 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: USHBP1 NM_031941.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.53

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08104098).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USHBP1	NM_031941.4	c.1772C>T	p.Ala591Val	missense_variant	11/13	ENST00000252597.8
USHBP1	NM_001321417.2	c.1772C>T	p.Ala591Val	missense_variant	11/13
USHBP1	NM_001297703.2	c.1580C>T	p.Ala527Val	missense_variant	10/12
USHBP1	NR_135632.2	n.2013C>T		non_coding_transcript_exon_variant	12/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USHBP1	ENST00000252597.8	c.1772C>T	p.Ala591Val	missense_variant	11/13	1	NM_031941.4	P1
USHBP1	ENST00000431146.6	c.1580C>T	p.Ala527Val	missense_variant	10/12	2
USHBP1	ENST00000324554.9	c.*738C>T		3_prime_UTR_variant, NMD_transcript_variant	12/14	2
USHBP1	ENST00000597928.5	c.*2892C>T		3_prime_UTR_variant, NMD_transcript_variant	10/12	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.17e-7 AC: 1 AN: 1394670 Hom.: 0 Cov.: 32 AF XY: 0.00000145 AC XY: 1 AN XY: 687998

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: 0.0000218

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 30, 2022

The c.1772C>T (p.A591V) alteration is located in exon 11 (coding exon 10) of the USHBP1 gene. This alteration results from a C to T substitution at nucleotide position 1772, causing the alanine (A) at amino acid position 591 to be replaced by a valine (V). 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	0.13
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	19
Dann	Uncertain	0.98
DEOGEN2	Benign	0.020	T;.
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.65	T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.081	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.032
Sift	Benign	0.12	T;D
Sift4G	Uncertain	0.025	D;D
Polyphen		0.27	B;.
Vest4		0.14
MutPred		0.24		Loss of disorder (P = 0.0622);.;
MVP		0.28
MPC		0.15
ClinPred		0.13	T
GERP RS		1.9
Varity_R		0.038
gMVP		0.094

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

Other links and lift over

dbSNP: rs2073558111; hg19: chr19-17362747;