19-17250400-G-T

Variant names:

• chr19-17250400-G-T
• rs142042090
• NM_031941.4:c.1937C>A

Variant summary

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

The NM_031941.4(USHBP1):​c.1937C>A​(p.Ala646Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000391 in 1,612,854 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: USHBP1 NM_031941.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.25
• 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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USHBP1	NM_031941.4	c.1937C>A	p.Ala646Asp	missense_variant	Exon 13 of 13	ENST00000252597.8	NP_114147.2
USHBP1	NM_001321417.2	c.1937C>A	p.Ala646Asp	missense_variant	Exon 13 of 13		NP_001308346.1
USHBP1	NM_001297703.2	c.1745C>A	p.Ala582Asp	missense_variant	Exon 12 of 12		NP_001284632.1
USHBP1	NR_135632.2	n.2178C>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.1937C>A	p.Ala646Asp	missense_variant	Exon 13 of 13	1	NM_031941.4	ENSP00000252597.2
ENSG00000269095	ENST00000594059.1	c.-83+1182C>A		intron_variant	Intron 3 of 4	4		ENSP00000473056.1

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000240 AC: 6 AN: 249794 AF XY: 0.0000148

Gnomad AFR exome AF: 0.000372

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000267 AC: 39 AN: 1460666 Hom.: 0 Cov.: 33 AF XY: 0.0000261 AC XY: 19 AN XY: 726710

African (AFR) AF: 0.000867 AC: 29 AN: 33454

American (AMR) AF: 0.0000224 AC: 1 AN: 44612

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52550

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111880

Other (OTH) AF: 0.000133 AC: 8 AN: 60376

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152188 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74344

African (AFR) AF: 0.000483 AC: 20 AN: 41446

American (AMR) AF: 0.000196 AC: 3 AN: 15278

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.0000489 Hom.: 0

Bravo AF: 0.000193

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 18, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1937C>A (p.A646D) 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 1937, causing the alanine (A) at amino acid position 646 to be replaced by an aspartic acid (D). 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	Pathogenic	0.62
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.73	T;T
M_CAP	Benign	0.027	D
MetaRNN	Uncertain	0.61	D;D
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.2	M;.
PhyloP100		3.2
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-4.0	D;D
REVEL	Benign	0.21
Sift	Uncertain	0.0040	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.75
MVP		0.31
MPC		0.79
ClinPred		0.76	D
GERP RS		3.5
Varity_R		0.67
gMVP		0.42
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs142042090; hg19: chr19-17361209;