rs11196400

chr10-113634189-C-T

Variant summary

Our verdict is Benign. Variant got -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 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 NM_198060.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.44

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

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	UniProt
NRAP	NM_198060.4	c.1450G>A	p.Asp484Asn	missense_variant	15/42	ENST00000359988.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NRAP	ENST00000359988.4	c.1450G>A	p.Asp484Asn	missense_variant	15/42	1	NM_198060.4	A1
NRAP	ENST00000369358.8	c.1450G>A	p.Asp484Asn	missense_variant	15/42	1		P5
NRAP	ENST00000360478.7	c.1345G>A	p.Asp449Asn	missense_variant	14/41	1
NRAP	ENST00000369360.7	c.1345G>A	p.Asp449Asn	missense_variant	14/41	5

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

GnomAD3 exomes AF: 0.150 AC: 37786 AN: 251254 Hom.: 3268 AF XY: 0.151 AC XY: 20460 AN XY: 135796

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

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.: 32 AF XY: 0.178 AC XY: 13211 AN XY: 74364

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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

NRAP-related condition Benign:1

Benign, criteria provided, single submitter

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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

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
Eigen	Benign	0.065
Eigen_PC	Benign	0.059
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.77	T;T;T;T
MetaRNN	Benign	0.0016	T;T;T;T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	0.0024	P;P;P;P;P
PrimateAI	Uncertain	0.56	T
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	T
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

Other links and lift over

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