chr10-68296284-C-A

Variant names:

• chr10-68296284-C-A
• rs141525509
• NM_022129.4:c.265G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_022129.4(PBLD):​c.265G>T​(p.Val89Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,104 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PBLD NM_022129.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.88
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.806

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PBLD	NM_022129.4	c.265G>T	p.Val89Leu	missense_variant	Exon 4 of 10	ENST00000358769.7	NP_071412.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PBLD	ENST00000358769.7	c.265G>T	p.Val89Leu	missense_variant	Exon 4 of 10	5	NM_022129.4	ENSP00000351619.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461104 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726882

African (AFR) AF: 0.0000299 AC: 1 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86206

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111416

Other (OTH) AF: 0.00 AC: 0 AN: 60366

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Benign	0.0051	T
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.048	T;T;T;.
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D;D;.;D
M_CAP	Benign	0.039	D
MetaRNN	Pathogenic	0.81	D;D;D;D
MetaSVM	Benign	-0.64	T
MutationAssessor	Pathogenic	3.0	.;M;M;M
PhyloP100		5.9
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-2.2	N;N;N;.
REVEL	Uncertain	0.31
Sift	Uncertain	0.011	D;D;D;.
Sift4G	Uncertain	0.017	D;D;D;D
Polyphen		0.99	.;D;D;.
Vest4		0.71
MutPred		0.80		.;Loss of methylation at K93 (P = 0.1105);Loss of methylation at K93 (P = 0.1105);Loss of methylation at K93 (P = 0.1105);
MVP		0.36
MPC		0.67
ClinPred		0.98	D
GERP RS		5.4
Varity_R		0.56
gMVP		0.78
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs141525509; hg19: chr10-70056041;