rs764849437

Variant names:

• chr19-17251636-C-T
• rs764849437
• NM_031941.4:c.1868G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_031941.4(USHBP1):​c.1868G>A​(p.Arg623Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,746 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000041 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: USHBP1 NM_031941.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.66
• Publications: 1 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14294952).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031941.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USHBP1	NM_031941.4	MANE Select	c.1868G>A	p.Arg623Gln	missense	Exon 12 of 13	NP_114147.2
	USHBP1	NM_001321417.2		c.1868G>A	p.Arg623Gln	missense	Exon 12 of 13	NP_001308346.1	Q8N6Y0-1
	USHBP1	NM_001297703.2		c.1676G>A	p.Arg559Gln	missense	Exon 11 of 12	NP_001284632.1	G8JLM4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USHBP1	ENST00000252597.8	TSL:1 MANE Select	c.1868G>A	p.Arg623Gln	missense	Exon 12 of 13	ENSP00000252597.2	Q8N6Y0-1
	ENSG00000269095	ENST00000594059.1	TSL:4	c.-137G>A		5_prime_UTR	Exon 3 of 5	ENSP00000473056.1	M0R384
	USHBP1	ENST00000881047.1		c.1868G>A	p.Arg623Gln	missense	Exon 11 of 12	ENSP00000551106.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152126 Hom.: 0 Cov.: 30

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251388 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461746 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727178

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53320

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111986

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000657 AC: 1 AN: 152126 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 74308

African (AFR) AF: 0.00 AC: 0 AN: 41434

American (AMR) AF: 0.00 AC: 0 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0094	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.061	N
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		1.7
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.67	N
REVEL	Benign	0.051
Sift	Benign	0.11	T
Sift4G	Benign	0.41	T
Polyphen		0.89	P
Vest4		0.36
MutPred		0.15		Gain of ubiquitination at K621 (P = 0.0213)
MVP		0.27
MPC		0.19
ClinPred		0.29	T
GERP RS		2.1
Varity_R		0.038
gMVP		0.10
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs764849437; hg19: chr19-17362445; COSMIC: COSV53102918;