rs1885434

chr10-113590838-G-Achr10-113590838-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_198060.4(NRAP):c.4696C>T(p.Arg1566Cys) variant causes a missense change. The variant allele was found at a frequency of 0.347 in 1,613,718 control chromosomes in the GnomAD database, including 98,739 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.37 (10708 hom., cov: 32)
  • Exomes 𝑓: 0.35 (88031 hom.)
• Consequence: NRAP NM_198060.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.61

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0027224123).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.453 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NRAP	NM_198060.4	c.4696C>T	p.Arg1566Cys	missense_variant	40/42	ENST00000359988.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NRAP	ENST00000359988.4	c.4696C>T	p.Arg1566Cys	missense_variant	40/42	1	NM_198060.4	A1
NRAP	ENST00000369358.8	c.4696C>T	p.Arg1566Cys	missense_variant	40/42	1		P5
NRAP	ENST00000360478.7	c.4591C>T	p.Arg1531Cys	missense_variant	39/41	1
NRAP	ENST00000369360.7	c.4615C>T	p.Arg1539Cys	missense_variant	39/41	5

Frequencies

GnomAD3 genomes AF: 0.370 AC: 56256 AN: 151934 Hom.: 10695 Cov.: 32

Gnomad AFR AF: 0.416

Gnomad AMI AF: 0.399

Gnomad AMR AF: 0.462

Gnomad ASJ AF: 0.340

Gnomad EAS AF: 0.319

Gnomad SAS AF: 0.321

Gnomad FIN AF: 0.294

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.343

Gnomad OTH AF: 0.365

GnomAD3 exomes AF: 0.359 AC: 89922 AN: 250634 Hom.: 16693 AF XY: 0.352 AC XY: 47639 AN XY: 135506

Gnomad AFR exome AF: 0.412

Gnomad AMR exome AF: 0.497

Gnomad ASJ exome AF: 0.347

Gnomad EAS exome AF: 0.306

Gnomad SAS exome AF: 0.322

Gnomad FIN exome AF: 0.299

Gnomad NFE exome AF: 0.340

Gnomad OTH exome AF: 0.355

GnomAD4 exome AF: 0.345 AC: 504358 AN: 1461666 Hom.: 88031 Cov.: 45 AF XY: 0.344 AC XY: 249784 AN XY: 727140

Gnomad4 AFR exome AF: 0.414

Gnomad4 AMR exome AF: 0.488

Gnomad4 ASJ exome AF: 0.345

Gnomad4 EAS exome AF: 0.314

Gnomad4 SAS exome AF: 0.320

Gnomad4 FIN exome AF: 0.301

Gnomad4 NFE exome AF: 0.342

Gnomad4 OTH exome AF: 0.345

GnomAD4 genome AF: 0.370 AC: 56310 AN: 152052 Hom.: 10708 Cov.: 32 AF XY: 0.368 AC XY: 27341 AN XY: 74332

Gnomad4 AFR AF: 0.416

Gnomad4 AMR AF: 0.462

Gnomad4 ASJ AF: 0.340

Gnomad4 EAS AF: 0.319

Gnomad4 SAS AF: 0.320

Gnomad4 FIN AF: 0.294

Gnomad4 NFE AF: 0.343

Gnomad4 OTH AF: 0.363

Alfa AF: 0.348 Hom.: 23281

Bravo AF: 0.383

TwinsUK AF: 0.337 AC: 1249

ALSPAC AF: 0.349 AC: 1344

ESP6500AA AF: 0.408 AC: 1797

ESP6500EA AF: 0.348 AC: 2996

ExAC AF: 0.353 AC: 42879

Asia WGS AF: 0.320 AC: 1112 AN: 3478

EpiCase AF: 0.336

EpiControl AF: 0.333

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	21
Dann	Uncertain	1.0
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.023
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D;D;D;D
MetaRNN	Benign	0.0027	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	0.00065	P;P;P;P;P
PrimateAI	Benign	0.27	T
PROVEAN	Pathogenic	-6.5	D;D;.;D
REVEL	Benign	0.11
Sift	Benign	0.039	D;D;.;D
Sift4G	Uncertain	0.015	D;D;D;D
Polyphen		0.024, 0.014	.;B;.;B
Vest4		0.30
MPC		0.097
ClinPred		0.077	T
GERP RS		3.8
Varity_R		0.23
gMVP		0.54

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: rs1885434; hg19: chr10-115350597; COSMIC: COSV63488229; COSMIC: COSV63488229;