1-154945049-C-T

Variant names:

• chr1-154945049-C-T
• NM_020524.4:c.2171G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_020524.4(PBXIP1):​c.2171G>A​(p.Ser724Asn) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PBXIP1 NM_020524.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.575

Genes affected

PBXIP1 (HGNC:21199): (PBX homeobox interacting protein 1) The protein encoded by this gene interacts with the PBX1 homeodomain protein, inhibiting its transcriptional activation potential by preventing its binding to DNA. The encoded protein, which is primarily cytosolic but can shuttle to the nucleus, also can interact with estrogen receptors alpha and beta and promote the proliferation of breast cancer, brain tumors, and lung cancer. Several transcript variants encoding different isoforms have been found for this gene. More variants exist, but their full-length natures have yet to be determined. [provided by RefSeq, Dec 2015]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.045063734).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PBXIP1	NM_020524.4	c.2171G>A	p.Ser724Asn	missense_variant	Exon 11 of 11	ENST00000368463.8	NP_065385.2
PBXIP1	NM_001317734.2	c.2084G>A	p.Ser695Asn	missense_variant	Exon 10 of 10		NP_001304663.1
PBXIP1	NM_001317735.2	c.1706G>A	p.Ser569Asn	missense_variant	Exon 8 of 8		NP_001304664.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PBXIP1	ENST00000368463.8	c.2171G>A	p.Ser724Asn	missense_variant	Exon 11 of 11	1	NM_020524.4	ENSP00000357448.3
PBXIP1	ENST00000368465.5	c.2084G>A	p.Ser695Asn	missense_variant	Exon 10 of 10	2		ENSP00000357450.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 27, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2171G>A (p.S724N) alteration is located in exon 11 (coding exon 10) of the PBXIP1 gene. This alteration results from a G to A substitution at nucleotide position 2171, causing the serine (S) at amino acid position 724 to be replaced by an asparagine (N). 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	0.092
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	1.2
DANN	Benign	0.74
DEOGEN2	Benign	0.0030	.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.36	T;T
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.045	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	.;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.21	N;N
REVEL	Benign	0.010
Sift	Benign	1.0	T;T
Sift4G	Benign	0.76	T;T
Polyphen		0.072	.;B
Vest4		0.11
MutPred		0.16		.;Loss of phosphorylation at S724 (P = 0.0113);
MVP		0.29
MPC		0.17
ClinPred		0.044	T
GERP RS		-2.8
Varity_R		0.017
gMVP		0.065

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-154917525;