10-113589078-C-G

Variant summary

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

The NM_198060.4(NRAP):​c.5090G>C​(p.Arg1697Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000403 in 1,613,398 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

NRAP
NM_198060.4 missense, splice_region

Scores

19
Splicing: ADA: 0.00005981
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.892
Variant links:
Genes affected
NRAP (HGNC:7988): (nebulin related anchoring protein) Predicted to enable actin filament binding activity and muscle alpha-actinin binding activity. Predicted to be involved in cardiac muscle thin filament assembly. Predicted to be located in fascia adherens; muscle tendon junction; and myofibril. Predicted to be active in Z disc. [provided by Alliance of Genome Resources, Apr 2022]
HABP2 (HGNC:4798): (hyaluronan binding protein 2) This gene encodes a member of the peptidase S1 family of serine proteases. The encoded preproprotein is secreted by hepatocytes and proteolytically processed to generate heavy and light chains that form the mature heterodimer. Further autoproteolysis leads to smaller, inactive peptides. This extracellular protease binds hyaluronic acid and may play a role in the coagulation and fibrinolysis systems. Mutations in this gene are associated with nonmedullary thyroid cancer and susceptibility to venous thromboembolism. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed. [provided by RefSeq, Jan 2016]

Genome browser will be placed here

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=0.08076817).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NRAPNM_198060.4 linkc.5090G>C p.Arg1697Pro missense_variant, splice_region_variant Exon 42 of 42 ENST00000359988.4 NP_932326.2 Q86VF7-1
HABP2NM_004132.5 linkc.*709C>G 3_prime_UTR_variant Exon 13 of 13 ENST00000351270.4 NP_004123.1 Q14520-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NRAPENST00000359988.4 linkc.5090G>C p.Arg1697Pro missense_variant, splice_region_variant Exon 42 of 42 1 NM_198060.4 ENSP00000353078.3 Q86VF7-1
HABP2ENST00000351270.4 linkc.*709C>G 3_prime_UTR_variant Exon 13 of 13 1 NM_004132.5 ENSP00000277903.4 Q14520-1

Frequencies

GnomAD3 genomes
AF:
0.0000592
AC:
9
AN:
152124
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.000118
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000399
AC:
10
AN:
250560
Hom.:
0
AF XY:
0.0000591
AC XY:
8
AN XY:
135424
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000796
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000383
AC:
56
AN:
1461274
Hom.:
0
Cov.:
31
AF XY:
0.0000413
AC XY:
30
AN XY:
726988
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000477
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000592
AC:
9
AN:
152124
Hom.:
0
Cov.:
32
AF XY:
0.0000807
AC XY:
6
AN XY:
74304
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000118
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.0000193
Hom.:
0
Bravo
AF:
0.0000567
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ExAC
AF:
0.0000412
AC:
5
EpiCase
AF:
0.000109
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Dec 23, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.5090G>C (p.R1697P) alteration is located in exon 42 (coding exon 42) of the NRAP gene. This alteration results from a G to C substitution at nucleotide position 5090, causing the arginine (R) at amino acid position 1697 to be replaced by a proline (P). 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
0.14
BayesDel_addAF
Benign
-0.51
T
BayesDel_noAF
Benign
-0.78
CADD
Benign
1.1
DANN
Benign
0.69
DEOGEN2
Benign
0.026
.;.;T;T
Eigen
Benign
-1.2
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.055
N
LIST_S2
Benign
0.40
T;T;T;T
M_CAP
Benign
0.0051
T
MetaRNN
Benign
0.081
T;T;T;T
MetaSVM
Benign
-0.97
T
MutationAssessor
Benign
0.0
.;.;.;N
PrimateAI
Benign
0.25
T
PROVEAN
Benign
-1.7
N;N;.;N
REVEL
Benign
0.018
Sift
Benign
0.28
T;T;.;T
Sift4G
Benign
0.25
T;T;T;T
Polyphen
0.0010
.;B;.;B
Vest4
0.073
MutPred
0.54
.;.;.;Loss of methylation at R1697 (P = 0.0185);
MVP
0.19
MPC
0.10
ClinPred
0.021
T
GERP RS
0.25
Varity_R
0.15
gMVP
0.60

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.000060
dbscSNV1_RF
Benign
0.0080
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

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

Other links and lift over

dbSNP: rs372444529; hg19: chr10-115348837; API