rs2275799

Positions:

• chr10-113650081-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.844G>A​(p.Ala282Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.266 in 1,607,864 control chromosomes in the GnomAD database, including 58,513 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict 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.

• Frequency:
  • Genomes: 𝑓 0.29 (6650 hom., cov: 32)
  • Exomes 𝑓: 0.26 (51863 hom.)
• Consequence: NRAP NM_198060.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.923

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=0.0042256117).
• BP6: Variant 10-113650081-C-T is Benign according to our data. Variant chr10-113650081-C-T is described in ClinVar as [Benign]. Clinvar id is 1273205.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.357 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NRAP	NM_198060.4	c.844G>A	p.Ala282Thr	missense_variant	9/42	ENST00000359988.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NRAP	ENST00000359988.4	c.844G>A	p.Ala282Thr	missense_variant	9/42	1	NM_198060.4	A1
NRAP	ENST00000369358.8	c.844G>A	p.Ala282Thr	missense_variant	9/42	1		P5
NRAP	ENST00000360478.7	c.844G>A	p.Ala282Thr	missense_variant	9/41	1
NRAP	ENST00000369360.7	c.844G>A	p.Ala282Thr	missense_variant	9/41	5

Frequencies

GnomAD3 genomes AF: 0.292 AC: 44423 AN: 151954 Hom.: 6648 Cov.: 32

Gnomad AFR AF: 0.363

Gnomad AMI AF: 0.271

Gnomad AMR AF: 0.245

Gnomad ASJ AF: 0.360

Gnomad EAS AF: 0.205

Gnomad SAS AF: 0.240

Gnomad FIN AF: 0.291

Gnomad MID AF: 0.383

Gnomad NFE AF: 0.267

Gnomad OTH AF: 0.290

GnomAD3 exomes AF: 0.264 AC: 66184 AN: 251110 Hom.: 9165 AF XY: 0.265 AC XY: 35932 AN XY: 135700

Gnomad AFR exome AF: 0.364

Gnomad AMR exome AF: 0.177

Gnomad ASJ exome AF: 0.369

Gnomad EAS exome AF: 0.210

Gnomad SAS exome AF: 0.250

Gnomad FIN exome AF: 0.296

Gnomad NFE exome AF: 0.271

Gnomad OTH exome AF: 0.286

GnomAD4 exome AF: 0.264 AC: 384051 AN: 1455792 Hom.: 51863 Cov.: 30 AF XY: 0.264 AC XY: 191291 AN XY: 724602

Gnomad4 AFR exome AF: 0.370

Gnomad4 AMR exome AF: 0.182

Gnomad4 ASJ exome AF: 0.362

Gnomad4 EAS exome AF: 0.195

Gnomad4 SAS exome AF: 0.251

Gnomad4 FIN exome AF: 0.300

Gnomad4 NFE exome AF: 0.262

Gnomad4 OTH exome AF: 0.274

GnomAD4 genome AF: 0.292 AC: 44444 AN: 152072 Hom.: 6650 Cov.: 32 AF XY: 0.289 AC XY: 21495 AN XY: 74312

Gnomad4 AFR AF: 0.362

Gnomad4 AMR AF: 0.245

Gnomad4 ASJ AF: 0.360

Gnomad4 EAS AF: 0.205

Gnomad4 SAS AF: 0.239

Gnomad4 FIN AF: 0.291

Gnomad4 NFE AF: 0.267

Gnomad4 OTH AF: 0.294

Alfa AF: 0.274 Hom.: 13603

Bravo AF: 0.292

TwinsUK AF: 0.270 AC: 1001

ALSPAC AF: 0.262 AC: 1010

ESP6500AA AF: 0.362 AC: 1595

ESP6500EA AF: 0.278 AC: 2389

ExAC AF: 0.267 AC: 32457

Asia WGS AF: 0.253 AC: 882 AN: 3478

EpiCase AF: 0.274

EpiControl AF: 0.279

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

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	Jan 10, 2019	This variant is associated with the following publications: (PMID: 27443559) -

NRAP-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 22, 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	0.069
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	17
DANN	Benign	0.94
DEOGEN2	Benign	0.022	.;.;T;T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.091
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.51	T;T;T;T
MetaRNN	Benign	0.0042	T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.9	L;L;.;L
MutationTaster	Benign	0.83	P;P;P;P;P
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.9	N;N;N;N
REVEL	Benign	0.12
Sift	Benign	0.32	T;T;T;T
Sift4G	Benign	0.40	T;T;T;T
Polyphen		0.036, 0.038	.;B;.;B
Vest4		0.018
MPC		0.079
ClinPred		0.019	T
GERP RS		5.2
Varity_R		0.067
gMVP		0.23

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: rs2275799; hg19: chr10-115409840; COSMIC: COSV63492370;