chr11-64246639-A-C

Variant names:

• chr11-64246639-A-C
• NM_138689.3:c.35T>G

Variant summary

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

The NM_138689.3(PPP1R14B):​c.35T>G​(p.Leu12Trp) 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: PPP1R14B NM_138689.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.97
• Publications: 0 publications found

Genes affected

PPP1R14B (HGNC:9057): (protein phosphatase 1 regulatory inhibitor subunit 14B) Predicted to enable protein serine/threonine phosphatase inhibitor activity. Predicted to be involved in innate immune response. Predicted to be located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

PPP1R14B-AS1 (HGNC:54233): (PPP1R14B antisense RNA 1)

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=0.2537905).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP1R14B	NM_138689.3	c.35T>G	p.Leu12Trp	missense_variant	Exon 1 of 4	ENST00000309318.8	NP_619634.1
PPP1R14B-AS1	NR_135087.1	n.224+550A>C		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP1R14B	ENST00000309318.8	c.35T>G	p.Leu12Trp	missense_variant	Exon 1 of 4	1	NM_138689.3	ENSP00000310117.3
PPP1R14B-AS1	ENST00000544553.4	n.253+550A>C		intron_variant	Intron 1 of 1	2
PPP1R14B-AS1	ENST00000663760.4	n.329+391A>C		intron_variant	Intron 1 of 1
PPP1R14B-AS1	ENST00000652899.2	n.-233A>C		upstream_gene_variant

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 18, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.35T>G (p.L12W) alteration is located in exon 1 (coding exon 1) of the PPP1R14B gene. This alteration results from a T to G substitution at nucleotide position 35, causing the leucine (L) at amino acid position 12 to be replaced by a tryptophan (W). 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	0.31
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Benign	0.10	T
Eigen	Benign	0.048
Eigen_PC	Benign	-0.015
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.50	T
M_CAP	Pathogenic	0.33	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	0.34	N
PhyloP100		2.0
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.86	N
REVEL	Benign	0.063
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.033	D
Polyphen		0.95	P
Vest4		0.23
MutPred		0.25		Gain of catalytic residue at P15 (P = 0.0334);
MVP		0.093
MPC		1.6
ClinPred		0.34	T
GERP RS		1.6
PromoterAI		-0.14	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.10
gMVP		0.34
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

hg19: chr11-64014111;