Genetic Variant UPK3BL1:p.Asp182His (chr7-102639141-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001114403.3(UPK3BL1):c.544G>C(p.Asp182His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D182N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000043 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

UPK3BL1
NM_001114403.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.324

Publications

0 publications found

Variant links:

Genes affected

UPK3BL1 (HGNC:37278): (uroplakin 3B like 1) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

UPK3BL1 links:

POLR2J2-UPK3BL1 (HGNC:58364):

POLR2J2-UPK3BL1 links:

ENSG00000205236 (HGNC:):

ENSG00000205236 links:

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ACMG classification

Classification was made for transcript

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=0.11476028).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001114403.3. 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
	UPK3BL1	NM_001114403.3	MANE Select	c.544G>C	p.Asp182His	missense	Exon 4 of 6	NP_001107875.1	B0FP48
	POLR2J2-UPK3BL1	NR_173352.1		n.896G>C		non_coding_transcript_exon	Exon 7 of 9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
UPK3BL1	ENST00000340457.8	TSL:1 MANE Select	c.544G>C	p.Asp182His	missense	Exon 4 of 6	ENSP00000342938.8	B0FP48
POLR2J2-UPK3BL1	ENST00000476151.5	TSL:1	n.*486G>C		non_coding_transcript_exon	Exon 7 of 9	ENSP00000418603.1
ENSG00000205236	ENST00000519541.1	TSL:2	n.544G>C		non_coding_transcript_exon	Exon 4 of 26	ENSP00000429397.1	A0A286YEE6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000430

AC:

AN:

1393800

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

687632

show subpopulations

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

African (AFR)

AF:

0.0000317

AC:

AN:

31584

American (AMR)

AF:

0.00

AC:

AN:

35590

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25080

East Asian (EAS)

AF:

0.0000841

AC:

AN:

35684

South Asian (SAS)

AF:

0.00

AC:

AN:

79098

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49294

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5674

European-Non Finnish (NFE)

AF:

0.00000186

AC:

AN:

1073942

Other (OTH)

AF:

0.00

AC:

AN:

57854

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000194751), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.342

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000612

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.027

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.0052

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.11

MetaSVM

Benign

-0.87

MutationAssessor

Benign

1.2

PhyloP100

-0.32

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-1.9

REVEL

Benign

0.073

Sift

Benign

0.050

Sift4G

Benign

0.067

Vest4

0.12

MutPred

0.37

Gain of MoRF binding (P = 0.1027)

MVP

0.030

ClinPred

0.16

GERP RS

0.65

Varity_R

0.045

gMVP

0.38

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over