rs138655196

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr5-57249559-C-T
• chr5-57249559-C-G

Variant summary

Our verdict is Benign. The variant received -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. 14/22 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
• Publications: 4 publications found

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

Our verdict: Benign. The variant received -8 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022913.4. 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
	GPBP1	NM_022913.4	MANE Select	c.955C>T	p.Arg319Cys	missense	Exon 9 of 12	NP_075064.1	Q86WP2-1
	GPBP1	NM_001331037.2		c.1015C>T	p.Arg339Cys	missense	Exon 10 of 13	NP_001317966.1	D4PHA4
	GPBP1	NM_001127236.2		c.976C>T	p.Arg326Cys	missense	Exon 8 of 11	NP_001120708.1	Q86WP2-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPBP1	ENST00000506184.7	TSL:1 MANE Select	c.955C>T	p.Arg319Cys	missense	Exon 9 of 12	ENSP00000421202.2	Q86WP2-1
	GPBP1	ENST00000264779.6	TSL:1	c.976C>T	p.Arg326Cys	missense	Exon 8 of 11	ENSP00000264779.6	Q86WP2-2
	GPBP1	ENST00000514387.6	TSL:1	c.442C>T	p.Arg148Cys	missense	Exon 8 of 11	ENSP00000421709.2	Q86WP2-4

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

GnomAD2 exomes AF: 0.000550 AC: 131 AN: 238148 AF XY: 0.000473

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 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

African (AFR) AF: 0.000152 AC: 5 AN: 32798

American (AMR) AF: 0.000928 AC: 38 AN: 40960

Ashkenazi Jewish (ASJ) AF: 0.00641 AC: 163 AN: 25440

East Asian (EAS) AF: 0.00 AC: 0 AN: 39566

South Asian (SAS) AF: 0.000215 AC: 18 AN: 83554

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53046

Middle Eastern (MID) AF: 0.000527 AC: 3 AN: 5692

European-Non Finnish (NFE) AF: 0.000137 AC: 152 AN: 1108842

Other (OTH) AF: 0.000735 AC: 44 AN: 59866

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

African (AFR) AF: 0.000266 AC: 11 AN: 41376

American (AMR) AF: 0.000590 AC: 9 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.00749 AC: 26 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

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

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 67996

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.000681 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

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	0.071
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
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.90	N
PhyloP100		1.7
PrimateAI	Benign	0.25	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.042
Sift	Benign	0.071	T
Sift4G	Benign	0.21	T
Polyphen		0.0010	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
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs138655196; hg19: chr5-56545386;