Genetic Variant UPK3BL1:p.Ile225Leu (chr7-102638724-T-G) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001114403.3(UPK3BL1):c.673A>C(p.Ile225Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00032 ( 0 hom., cov: 25)

Exomes 𝑓: 0.00021 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

UPK3BL1
NM_001114403.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.191

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:

ENSG00000267645 (HGNC:):

ENSG00000267645 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.05464086).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UPK3BL1	NM_001114403.3 link	c.673A>C	p.Ile225Leu	missense_variant	Exon 5 of 6	ENST00000340457.8	NP_001107875.1	B0FP48E5RIL1
POLR2J2-UPK3BL1	NR_173352.1 link	n.1025A>C		non_coding_transcript_exon_variant	Exon 8 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
UPK3BL1	ENST00000340457.8 link	c.673A>C	p.Ile225Leu	missense_variant	Exon 5 of 6	1	NM_001114403.3	ENSP00000342938.8	B0FP48
ENSG00000267645	ENST00000476151.5 link	n.*615A>C		non_coding_transcript_exon_variant	Exon 8 of 9	1		ENSP00000418603.1
ENSG00000205236	ENST00000519541.1 link	n.673A>C		non_coding_transcript_exon_variant	Exon 5 of 26	2		ENSP00000429397.1	A0A286YEE6
ENSG00000267645	ENST00000476151.5 link	n.*615A>C		3_prime_UTR_variant	Exon 8 of 9	1		ENSP00000418603.1

Frequencies

GnomAD3 genomes

AF:

0.000308

AC:

AN:

145874

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000694

Gnomad ASJ

AF:

0.00238

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000461

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000351

Gnomad OTH

AF:

0.00101

GnomAD3 exomes

AF:

0.000139

AC:

AN:

57436

Hom.:

AF XY:

0.000206

AC XY:

AN XY:

29136

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000177

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000759

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000509

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000214

AC:

206

AN:

962768

Hom.:

Cov.:

AF XY:

0.000245

AC XY:

117

AN XY:

478456

show subpopulations

Gnomad4 AFR exome

AF:

0.0000814

Gnomad4 AMR exome

AF:

0.000174

Gnomad4 ASJ exome

AF:

0.000815

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000922

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000161

Gnomad4 OTH exome

AF:

0.000256

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000315

AC:

AN:

145996

Hom.:

Cov.:

AF XY:

0.000367

AC XY:

AN XY:

70904

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000693

Gnomad4 ASJ

AF:

0.00238

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000461

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000351

Gnomad4 OTH

AF:

0.000996

Alfa

AF:

0.000429

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 10, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.673A>C (p.I225L) alteration is located in exon 5 (coding exon 5) of the UPK3BL gene. This alteration results from a A to C substitution at nucleotide position 673, causing the isoleucine (I) at amino acid position 225 to be replaced by a leucine (L). 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

0.11

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.025

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.059

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.055

MetaSVM

Benign

-0.86

MutationAssessor

Benign

1.5

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.85

REVEL

Benign

0.037

Sift

Benign

0.071

Sift4G

Benign

0.14

Vest4

0.28

MutPred

0.31

Loss of catalytic residue at I225 (P = 0.0562);

MVP

0.040

ClinPred

0.016

GERP RS

0.78

Varity_R

0.051

gMVP

0.24

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over