7-154954414-T-C

Variant names:

• chr7-154954414-T-C
• rs1190574141
• NM_007349.4:c.2662A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_007349.4(PAXIP1):​c.2662A>G​(p.Ile888Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000583 in 1,543,274 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: PAXIP1 NM_007349.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.42
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.166221).

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>G	p.Ile888Val	missense	Exon 16 of 21	NP_031375.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAXIP1	ENST00000404141.6	TSL:5 MANE Select	c.2662A>G	p.Ile888Val	missense	Exon 16 of 21	ENSP00000384048.1	Q6ZW49-6
	PAXIP1	ENST00000919354.1		c.2440A>G	p.Ile814Val	missense	Exon 13 of 18	ENSP00000589413.1
	PAXIP1	ENST00000457196.5	TSL:5	n.*2381A>G		non_coding_transcript_exon	Exon 17 of 22	ENSP00000392011.1	F8WC23

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 151912 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000877 AC: 2 AN: 228048 AF XY: 0.0000160

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000352

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000944

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000359 AC: 5 AN: 1391362 Hom.: 0 Cov.: 31 AF XY: 0.00000436 AC XY: 3 AN XY: 687428

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

African (AFR) AF: 0.00 AC: 0 AN: 31446

American (AMR) AF: 0.0000255 AC: 1 AN: 39182

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24480

East Asian (EAS) AF: 0.00 AC: 0 AN: 37866

South Asian (SAS) AF: 0.00 AC: 0 AN: 78302

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5496

European-Non Finnish (NFE) AF: 0.00000375 AC: 4 AN: 1066556

Other (OTH) AF: 0.00 AC: 0 AN: 56676

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00160812), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 151912 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74170

African (AFR) AF: 0.0000242 AC: 1 AN: 41344

American (AMR) AF: 0.00 AC: 0 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67964

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000302

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	14
DANN	Benign	0.62
DEOGEN2	Benign	0.088	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.58
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	0.90	L
PhyloP100		2.4
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.060	N
REVEL	Benign	0.13
Sift	Benign	0.53	T
Sift4G	Uncertain	0.049	D
Polyphen		0.0	B
Vest4		0.29
MutPred		0.44		Gain of loop (P = 0.1069)
MVP		0.45
MPC		0.68
ClinPred		0.019	T
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.078
gMVP		0.13
Mutation Taster		=72/28	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: rs1190574141; hg19: chr7-154746124;