chr10-68292037-G-T

Variant names:

• chr10-68292037-G-T
• rs779183526
• NM_022129.4:c.396C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_022129.4(PBLD):​c.396C>A​(p.Asp132Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000654 in 1,590,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000069 (0 hom.)
• Consequence: PBLD NM_022129.4 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.129
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0872581).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PBLD	NM_022129.4	c.396C>A	p.Asp132Glu	missense_variant, splice_region_variant	Exon 6 of 10	ENST00000358769.7	NP_071412.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PBLD	ENST00000358769.7	c.396C>A	p.Asp132Glu	missense_variant, splice_region_variant	Exon 6 of 10	5	NM_022129.4	ENSP00000351619.2

Frequencies

GnomAD3 genomes AF: 0.0000331 AC: 5 AN: 150870 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000739

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000644 AC: 16 AN: 248442 AF XY: 0.0000818

Gnomad AFR exome AF: 0.00

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: 0.000124

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000688 AC: 99 AN: 1439986 Hom.: 0 Cov.: 29 AF XY: 0.0000655 AC XY: 47 AN XY: 717476

African (AFR) AF: 0.00 AC: 0 AN: 33026

American (AMR) AF: 0.00 AC: 0 AN: 44458

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25992

East Asian (EAS) AF: 0.00 AC: 0 AN: 39594

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85644

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5732

European-Non Finnish (NFE) AF: 0.0000879 AC: 96 AN: 1092422

Other (OTH) AF: 0.0000167 AC: 1 AN: 59708

GnomAD4 genome AF: 0.0000331 AC: 5 AN: 150870 Hom.: 0 Cov.: 32 AF XY: 0.0000408 AC XY: 3 AN XY: 73532

African (AFR) AF: 0.00 AC: 0 AN: 41364

American (AMR) AF: 0.00 AC: 0 AN: 14940

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3442

East Asian (EAS) AF: 0.00 AC: 0 AN: 5136

South Asian (SAS) AF: 0.00 AC: 0 AN: 4644

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10364

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

European-Non Finnish (NFE) AF: 0.0000739 AC: 5 AN: 67692

Other (OTH) AF: 0.00 AC: 0 AN: 2070

Alfa AF: 0.0000564 Hom.: 0

Bravo AF: 0.0000491

ExAC AF: 0.0000494 AC: 6

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 11, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.396C>A (p.D132E) alteration is located in exon 6 (coding exon 5) of the PBLD gene. This alteration results from a C to A substitution at nucleotide position 396, causing the aspartic acid (D) at amino acid position 132 to be replaced by a glutamic acid (E). 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	0.13
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.021	T;T;T;.
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.48	T;T;.;T
M_CAP	Benign	0.0073	T
MetaRNN	Benign	0.087	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.74	.;N;N;N
PhyloP100		0.13
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.1	N;N;N;.
REVEL	Benign	0.032
Sift	Benign	0.37	T;T;T;.
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0010	.;B;B;.
Vest4		0.15
MutPred		0.41		.;Gain of disorder (P = 0.1087);Gain of disorder (P = 0.1087);Gain of disorder (P = 0.1087);
MVP		0.26
MPC		0.16
ClinPred		0.070	T
GERP RS		3.3
Varity_R		0.099
gMVP		0.46
Mutation Taster		=97/3	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: rs779183526; hg19: chr10-70051794;