rs11196400

Variant names:

• chr10-113634189-C-T
• rs11196400
• NM_198060.4:c.1450G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_198060.4(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 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 NM_198060.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 5.44
• Publications: 26 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198060.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRAP	NM_198060.4	MANE Select	c.1450G>A	p.Asp484Asn	missense	Exon 15 of 42	NP_932326.2
	NRAP	NM_001261463.2		c.1450G>A	p.Asp484Asn	missense	Exon 15 of 42	NP_001248392.1
	NRAP	NM_006175.5		c.1345G>A	p.Asp449Asn	missense	Exon 14 of 41	NP_006166.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRAP	ENST00000359988.4	TSL:1 MANE Select	c.1450G>A	p.Asp484Asn	missense	Exon 15 of 42	ENSP00000353078.3
	NRAP	ENST00000369358.8	TSL:1	c.1450G>A	p.Asp484Asn	missense	Exon 15 of 42	ENSP00000358365.4
	NRAP	ENST00000360478.7	TSL:1	c.1345G>A	p.Asp449Asn	missense	Exon 14 of 41	ENSP00000353666.3

Frequencies

GnomAD3 genomes AF: 0.179 AC: 27231 AN: 151946 Hom.: 2963 Cov.: 32

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

GnomAD2 exomes AF: 0.150 AC: 37786 AN: 251254 AF XY: 0.151

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 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.: 30 AF XY: 0.131 AC XY: 95334 AN XY: 726142

African (AFR) AF: 0.309 AC: 10311 AN: 33406

American (AMR) AF: 0.102 AC: 4575 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.244 AC: 6373 AN: 26106

East Asian (EAS) AF: 0.145 AC: 5734 AN: 39672

South Asian (SAS) AF: 0.174 AC: 14957 AN: 86158

European-Finnish (FIN) AF: 0.145 AC: 7750 AN: 53410

Middle Eastern (MID) AF: 0.227 AC: 1307 AN: 5758

European-Non Finnish (NFE) AF: 0.116 AC: 129207 AN: 1109896

Other (OTH) AF: 0.153 AC: 9220 AN: 60272

GnomAD4 genome AF: 0.179 AC: 27249 AN: 152064 Hom.: 2965 Cov.: 32 AF XY: 0.178 AC XY: 13211 AN XY: 74364

African (AFR) AF: 0.298 AC: 12358 AN: 41442

American (AMR) AF: 0.140 AC: 2133 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.230 AC: 797 AN: 3466

East Asian (EAS) AF: 0.158 AC: 816 AN: 5172

South Asian (SAS) AF: 0.160 AC: 769 AN: 4810

European-Finnish (FIN) AF: 0.136 AC: 1443 AN: 10590

Middle Eastern (MID) AF: 0.271 AC: 79 AN: 292

European-Non Finnish (NFE) AF: 0.123 AC: 8362 AN: 68002

Other (OTH) AF: 0.191 AC: 404 AN: 2110

Alfa AF: 0.146 Hom.: 7442

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

May 05, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NRAP-related disorder Benign:1

Nov 08, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Benign	0.065
Eigen_PC	Benign	0.059
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		5.4
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.14
Sift	Benign	0.032	D
Sift4G	Benign	0.084	T
Polyphen		0.96	D
Vest4		0.13
MPC		0.42
ClinPred		0.056	T
GERP RS		4.3
Varity_R		0.30
gMVP		0.60
Mutation Taster		=99/1	polymorphism (auto)

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: rs11196400; hg19: chr10-115393948; COSMIC: COSV63492339;