Genetic Variant NM_007349.4:c.2662A>T (chr7-154954414-T-A) – 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_007349.4(PAXIP1):c.2662A>T(p.Ile888Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000719 in 1,391,362 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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. I888V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

PAXIP1
NM_007349.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.42

Publications

0 publications found

Variant links:

Genes affected

PAXIP1 (HGNC:8624): (PAX interacting protein 1) This gene is a member of the paired box (PAX) gene family and encodes a nuclear protein with six BRCT (breast cancer carboxy-terminal) domains. This protein plays a critical role in maintaining genome stability, condensation of chromatin and progression through mitosis. [provided by RefSeq, Jul 2008]

PAXIP1 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=0.19821602).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007349.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAXIP1	NM_007349.4	MANE Select	c.2662A>T	p.Ile888Phe	missense	Exon 16 of 21	NP_031375.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PAXIP1	ENST00000404141.6	TSL:5 MANE Select	c.2662A>T	p.Ile888Phe	missense	Exon 16 of 21	ENSP00000384048.1	Q6ZW49-6
PAXIP1	ENST00000919354.1		c.2440A>T	p.Ile814Phe	missense	Exon 13 of 18	ENSP00000589413.1
PAXIP1	ENST00000457196.5	TSL:5	n.*2381A>T		non_coding_transcript_exon	Exon 17 of 22	ENSP00000392011.1	F8WC23

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.19e-7

AC:

AN:

1391362

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

687428

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

31446

American (AMR)

AF:

0.00

AC:

AN:

39182

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24480

East Asian (EAS)

AF:

0.00

AC:

AN:

37866

South Asian (SAS)

AF:

0.0000128

AC:

AN:

78302

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51358

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5496

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1066556

Other (OTH)

AF:

0.00

AC:

AN:

56676

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.084

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Benign

0.75

DEOGEN2

Benign

0.17

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.39

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.86

M_CAP

Benign

0.059

MetaRNN

Benign

0.20

MetaSVM

Benign

-0.77

MutationAssessor

Benign

0.35

PhyloP100

2.4

PrimateAI

Benign

0.48

PROVEAN

Benign

-1.7

REVEL

Benign

0.22

Sift

Benign

0.83

Sift4G

Uncertain

0.0060

Polyphen

0.0040

Vest4

0.35

MutPred

0.46

Gain of ubiquitination at K885 (P = 0.1504)

MVP

0.64

MPC

1.3

ClinPred

0.31

GERP RS

2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.26

gMVP

0.29

Mutation Taster

=59/41

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over