5-57249559-C-T

Variant names:

• chr5-57249559-C-T
• rs138655196
• NM_022913.4:c.955C>T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_022913.4(GPBP1):​c.955C>T​(p.Arg319Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000305 in 1,601,760 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R319H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00029 (2 hom.)
• Consequence: GPBP1 NM_022913.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.66

Genes affected

GPBP1 (HGNC:29520): (GC-rich promoter binding protein 1) This gene was originally isolated by subtractive hybridization of cDNAs expressed in atherosclerotic plaques with a thrombus, and was found to be expressed only in vascular smooth muscle cells. However, a shorter splice variant was found to be more ubiquitously expressed. This protein is suggested to play a role in the development of atherosclerosis. Studies in mice suggest that it may also function as a GC-rich promoter-specific trans-activating transcription factor. Several alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Feb 2011]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0034926832).
• BS2: High Homozygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPBP1	NM_022913.4	c.955C>T	p.Arg319Cys	missense_variant	Exon 9 of 12	ENST00000506184.7	NP_075064.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPBP1	ENST00000506184.7	c.955C>T	p.Arg319Cys	missense_variant	Exon 9 of 12	1	NM_022913.4	ENSP00000421202.2

Frequencies

GnomAD3 genomes AF: 0.000434 AC: 66 AN: 151996 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000590

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000550 AC: 131 AN: 238148 Hom.: 0 AF XY: 0.000473 AC XY: 61 AN XY: 128906

Gnomad AFR exome AF: 0.000187

Gnomad AMR exome AF: 0.000820

Gnomad ASJ exome AF: 0.00709

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000182

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000227

Gnomad OTH exome AF: 0.00139

GnomAD4 exome AF: 0.000292 AC: 423 AN: 1449764 Hom.: 2 Cov.: 30 AF XY: 0.000305 AC XY: 220 AN XY: 720972

Gnomad4 AFR exome AF: 0.000152

Gnomad4 AMR exome AF: 0.000928

Gnomad4 ASJ exome AF: 0.00641

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000215

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000137

Gnomad4 OTH exome AF: 0.000735

GnomAD4 genome AF: 0.000434 AC: 66 AN: 151996 Hom.: 0 Cov.: 31 AF XY: 0.000377 AC XY: 28 AN XY: 74230

Gnomad4 AFR AF: 0.000266

Gnomad4 AMR AF: 0.000590

Gnomad4 ASJ AF: 0.00749

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000692 Hom.: 0

Bravo AF: 0.000472

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000461 AC: 56

EpiCase AF: 0.000437

EpiControl AF: 0.000238

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 22, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.976C>T (p.R326C) alteration is located in exon 8 (coding exon 8) of the GPBP1 gene. This alteration results from a C to T substitution at nucleotide position 976, causing the arginine (R) at amino acid position 326 to be replaced by a cysteine (C). 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	0.071
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.50
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0062	.;.;T;.;.
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.012
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.88	D;D;D;D;D
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.0035	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.90	.;.;N;.;.
PrimateAI	Benign	0.25	T
PROVEAN	Benign	1.1	N;N;N;N;N
REVEL	Benign	0.042
Sift	Benign	0.071	T;T;T;T;T
Sift4G	Benign	0.21	T;T;T;T;T
Polyphen		0.0010	B;.;B;B;B
Vest4		0.20
MVP		0.043
MPC		0.46
ClinPred		0.019	T
GERP RS		5.3
Varity_R		0.069
gMVP		0.46

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

LitVar

Other links and lift over

dbSNP: rs138655196; hg19: chr5-56545386;