NM_017906.3:c.380C>G

Variant names:

• chr6-10702576-C-G
• NM_017906.3:c.380C>G

Variant summary

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

The NM_017906.3(PAK1IP1):​c.380C>G​(p.Thr127Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAK1IP1 NM_017906.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.20
• Publications: 0 publications found

Genes affected

PAK1IP1 (HGNC:20882): (PAK1 interacting protein 1) Involved in regulation of signal transduction by p53 class mediator and ribosomal large subunit biogenesis. Located in nucleolus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAK1IP1	NM_017906.3	c.380C>G	p.Thr127Ser	missense_variant	Exon 4 of 10	ENST00000379568.4	NP_060376.2
PAK1IP1	XM_011514721.1	c.446C>G	p.Thr149Ser	missense_variant	Exon 5 of 11		XP_011513023.1
PAK1IP1	XM_005249204.3	c.383C>G	p.Thr128Ser	missense_variant	Exon 4 of 10		XP_005249261.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAK1IP1	ENST00000379568.4	c.380C>G	p.Thr127Ser	missense_variant	Exon 4 of 10	1	NM_017906.3	ENSP00000368887.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 24, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.380C>G (p.T127S) alteration is located in exon 4 (coding exon 4) of the PAK1IP1 gene. This alteration results from a C to G substitution at nucleotide position 380, causing the threonine (T) at amino acid position 127 to be replaced by a serine (S). 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	0.10
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.026	T
Eigen	Benign	-0.061
Eigen_PC	Benign	0.17
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.56	N
PhyloP100		4.2
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.076
Sift	Benign	0.20	T
Sift4G	Benign	0.42	T
Polyphen		0.044	B
Vest4		0.40
MutPred		0.67		Gain of disorder (P = 0.0401);
MVP		0.25
MPC		0.16
ClinPred		0.54	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.10
gMVP		0.27
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.23		Position offset: -11

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr6-10702809;