Genetic Variant GPBP1L1:p.Lys148Asn (chr1-45654576-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_021639.5(GPBP1L1):c.444G>C(p.Lys148Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,460,184 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

GPBP1L1
NM_021639.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.46

Variant links:

Genes affected

GPBP1L1 (HGNC:28843): (GC-rich promoter binding protein 1 like 1) Predicted to enable DNA binding activity and RNA binding activity. Predicted to be involved in regulation of transcription, DNA-templated. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

GPBP1L1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.23110321).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPBP1L1	NM_021639.5 link	c.444G>C	p.Lys148Asn	missense_variant	Exon 6 of 13	ENST00000355105.8	NP_067652.1	Q9HC44

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GPBP1L1	ENST00000355105.8 link	c.444G>C	p.Lys148Asn	missense_variant	Exon 6 of 13	1	NM_021639.5	ENSP00000347224.3	Q9HC44
GPBP1L1	ENST00000290795.7 link	c.444G>C	p.Lys148Asn	missense_variant	Exon 5 of 12	5		ENSP00000290795.3	Q9HC44
GPBP1L1	ENST00000496278.1 link	n.1224G>C		non_coding_transcript_exon_variant	Exon 2 of 2	2
GPBP1L1	ENST00000498128.1 link	n.311G>C		non_coding_transcript_exon_variant	Exon 2 of 4	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000598

AC:

AN:

250884

Hom.:

AF XY:

0.0000369

AC XY:

AN XY:

135584

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000434

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1460184

Hom.:

Cov.:

AF XY:

0.00000964

AC XY:

AN XY:

726068

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000403

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.444G>C (p.K148N) alteration is located in exon 6 (coding exon 3) of the GPBP1L1 gene. This alteration results from a G to C substitution at nucleotide position 444, causing the lysine (K) at amino acid position 148 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

0.29

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

T;T

Eigen

Benign

0.053

Eigen_PC

Benign

0.052

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.74

.;T

M_CAP

Benign

0.021

MetaRNN

Benign

0.23

T;T

MetaSVM

Benign

-0.74

MutationAssessor

Uncertain

2.1

M;M

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-2.6

D;D

REVEL

Benign

0.11

Sift

Uncertain

0.0030

D;D

Sift4G

Benign

0.074

T;T

Polyphen

0.84

P;P

Vest4

0.52

MutPred

0.16

Loss of ubiquitination at K148 (P = 0.0087);Loss of ubiquitination at K148 (P = 0.0087);

MVP

0.53

MPC

0.44

ClinPred

0.29

GERP RS

2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.46

gMVP

0.18

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over