Genetic Variant PBLD:p.Arg275Lys (chr10-68284220-C-T) – 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_022129.4(PBLD):c.824G>A(p.Arg275Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. R275T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PBLD
NM_022129.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.625

Publications

0 publications found

Variant links:

Genes affected

PBLD (HGNC:23301): (phenazine biosynthesis like protein domain containing) Enables identical protein binding activity. Involved in maintenance of gastrointestinal epithelium; negative regulation of SMAD protein signal transduction; and negative regulation of transforming growth factor beta receptor signaling pathway. Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

PBLD 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=0.2224307).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PBLD	NM_022129.4 link	c.824G>A	p.Arg275Lys	missense_variant	Exon 10 of 10	ENST00000358769.7	NP_071412.2	P30039-1A0A024QZK5
PBLD	XM_005270028.5 link	c.824G>A	p.Arg275Lys	missense_variant	Exon 10 of 10		XP_005270085.1	P30039-1A0A024QZK5
PBLD	XM_011540060.4 link	c.799G>A	p.Glu267Lys	missense_variant	Exon 10 of 10		XP_011538362.1
PBLD	XM_017016513.2 link	c.799G>A	p.Glu267Lys	missense_variant	Exon 10 of 10		XP_016872002.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PBLD	ENST00000358769.7 link	c.824G>A	p.Arg275Lys	missense_variant	Exon 10 of 10	5	NM_022129.4	ENSP00000351619.2	P30039-1
PBLD	ENST00000309049.8 link	c.824G>A	p.Arg275Lys	missense_variant	Exon 10 of 10	1		ENSP00000308466.4	P30039-1
PBLD	ENST00000336578.5 link	c.725G>A	p.Arg242Lys	missense_variant	Exon 8 of 8	1		ENSP00000338041.1	A0A0C4DFS0
PBLD	ENST00000468798.5 link	c.212-930G>A		intron_variant	Intron 2 of 2	3		ENSP00000476261.1	V9GY00

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461846

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111988

Other (OTH)

AF:

0.00

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.76

CADD

Benign

0.53

(source)

DANN

Benign

0.51

DEOGEN2

Benign

0.0091

T;T;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0098

LIST_S2

Benign

0.62

T;T;.

M_CAP

Benign

0.0048

MetaRNN

Benign

0.22

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.52

.;N;N

PhyloP100

-0.63

PrimateAI

Benign

0.30

PROVEAN

Benign

0.13

N;N;N

REVEL

Benign

0.011

Sift

Benign

0.58

T;T;T

Sift4G

Benign

0.51

T;T;T

Polyphen

0.0

.;B;B

Vest4

0.032

MutPred

0.51

.;Loss of methylation at R275 (P = 0.0159);Loss of methylation at R275 (P = 0.0159);

MVP

0.14

MPC

0.17

ClinPred

0.017

GERP RS

-3.8

Varity_R

0.060

gMVP

0.51

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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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10-68284220-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over