rs11196400

Positions:

chr10-113634189-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000359988.4(NRAP):c.1450G>A(p.Asp484Asn) variant causes a missense change. The variant allele was found at a frequency of 0.134 in 1,611,454 control chromosomes in the GnomAD database, including 16,538 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D484E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.18 ( 2965 hom., cov: 32)

Exomes 𝑓: 0.13 ( 13573 hom. )

Consequence

NRAP
ENST00000359988.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 5.44

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]

NRAP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0016168356).

BP6

Variant 10-113634189-C-T is Benign according to our data. Variant chr10-113634189-C-T is described in ClinVar as [Benign]. Clinvar id is 1288561.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.294 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NRAP	NM_198060.4 linkuse as main transcript	c.1450G>A	p.Asp484Asn	missense_variant	15/42	ENST00000359988.4	NP_932326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NRAP	ENST00000359988.4 linkuse as main transcript	c.1450G>A	p.Asp484Asn	missense_variant	15/42	1	NM_198060.4	ENSP00000353078	A1	Q86VF7-1
NRAP	ENST00000369358.8 linkuse as main transcript	c.1450G>A	p.Asp484Asn	missense_variant	15/42	1		ENSP00000358365	P5
NRAP	ENST00000360478.7 linkuse as main transcript	c.1345G>A	p.Asp449Asn	missense_variant	14/41	1		ENSP00000353666		Q86VF7-4
NRAP	ENST00000369360.7 linkuse as main transcript	c.1345G>A	p.Asp449Asn	missense_variant	14/41	5		ENSP00000358367		Q86VF7-3

Frequencies

GnomAD3 genomes

AF:

0.179

AC:

27231

AN:

151946

Hom.:

2963

Cov.:

show subpopulations

Gnomad AFR

AF:

0.299

Gnomad AMI

AF:

0.0967

Gnomad AMR

AF:

0.140

Gnomad ASJ

AF:

0.230

Gnomad EAS

AF:

0.157

Gnomad SAS

AF:

0.159

Gnomad FIN

AF:

0.136

Gnomad MID

AF:

0.264

Gnomad NFE

AF:

0.123

Gnomad OTH

AF:

0.191

GnomAD3 exomes

AF:

0.150

AC:

37786

AN:

251254

Hom.:

3268

AF XY:

0.151

AC XY:

20460

AN XY:

135796

show subpopulations

Gnomad AFR exome

AF:

0.304

Gnomad AMR exome

AF:

0.0995

Gnomad ASJ exome

AF:

0.250

Gnomad EAS exome

AF:

0.158

Gnomad SAS exome

AF:

0.174

Gnomad FIN exome

AF:

0.141

Gnomad NFE exome

AF:

0.129

Gnomad OTH exome

AF:

0.161

GnomAD4 exome

AF:

0.130

AC:

189434

AN:

1459390

Hom.:

13573

Cov.:

AF XY:

0.131

AC XY:

95334

AN XY:

726142

show subpopulations

Gnomad4 AFR exome

AF:

0.309

Gnomad4 AMR exome

AF:

0.102

Gnomad4 ASJ exome

AF:

0.244

Gnomad4 EAS exome

AF:

0.145

Gnomad4 SAS exome

AF:

0.174

Gnomad4 FIN exome

AF:

0.145

Gnomad4 NFE exome

AF:

0.116

Gnomad4 OTH exome

AF:

0.153

GnomAD4 genome

AF:

0.179

AC:

27249

AN:

152064

Hom.:

2965

Cov.:

AF XY:

0.178

AC XY:

13211

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.298

Gnomad4 AMR

AF:

0.140

Gnomad4 ASJ

AF:

0.230

Gnomad4 EAS

AF:

0.158

Gnomad4 SAS

AF:

0.160

Gnomad4 FIN

AF:

0.136

Gnomad4 NFE

AF:

0.123

Gnomad4 OTH

AF:

0.191

Alfa

AF:

0.139

Hom.:

4256

Bravo

AF:

0.185

TwinsUK

AF:

0.122

AC:

454

ALSPAC

AF:

0.116

AC:

447

ESP6500AA

AF:

0.296

AC:

1305

ESP6500EA

AF:

0.133

AC:

1141

ExAC

AF:

0.154

AC:

18725

Asia WGS

AF:

0.176

AC:

614

AN:

3478

EpiCase

AF:

0.135

EpiControl

AF:

0.139

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	- -

NRAP-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 08, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.65

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.16

.;.;T;T

Eigen

Benign

0.065

Eigen_PC

Benign

0.059

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.77

T;T;T;T

MetaRNN

Benign

0.0016

T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Uncertain

2.3

.;.;.;M

MutationTaster

Benign

0.0024

P;P;P;P;P

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-3.6

D;D;D;D

REVEL

Benign

0.14

Sift

Benign

0.032

D;D;D;D

Sift4G

Benign

0.084

T;T;T;T

Polyphen

0.96, 0.94

.;D;.;P

Vest4

0.13

MPC

0.42

ClinPred

0.056

GERP RS

4.3

Varity_R

0.30

gMVP

0.60

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

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