rs2286735

Positions:

• chr10-113629607-G-A

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.2021C>T​(p.Ala674Val) variant causes a missense change. The variant allele was found at a frequency of 0.308 in 1,607,510 control chromosomes in the GnomAD database, including 78,212 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.

• Frequency:
  • Genomes: 𝑓 0.28 (6360 hom., cov: 32)
  • Exomes 𝑓: 0.31 (71852 hom.)
• Consequence: NRAP NM_198060.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 6.92

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=0.0049262047).
• BP6: Variant 10-113629607-G-A is Benign according to our data. Variant chr10-113629607-G-A is described in ClinVar as [Benign]. Clinvar id is 1269749.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.35 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NRAP	NM_198060.4	c.2021C>T	p.Ala674Val	missense_variant	19/42	ENST00000359988.4	NP_932326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NRAP	ENST00000359988.4	c.2021C>T	p.Ala674Val	missense_variant	19/42	1	NM_198060.4	ENSP00000353078	A1
NRAP	ENST00000369358.8	c.2021C>T	p.Ala674Val	missense_variant	19/42	1		ENSP00000358365	P5
NRAP	ENST00000360478.7	c.1916C>T	p.Ala639Val	missense_variant	18/41	1		ENSP00000353666
NRAP	ENST00000369360.7	c.1940C>T	p.Ala647Val	missense_variant	18/41	5		ENSP00000358367

Frequencies

GnomAD3 genomes AF: 0.285 AC: 43185 AN: 151752 Hom.: 6338 Cov.: 32

Gnomad AFR AF: 0.215

Gnomad AMI AF: 0.219

Gnomad AMR AF: 0.358

Gnomad ASJ AF: 0.291

Gnomad EAS AF: 0.286

Gnomad SAS AF: 0.297

Gnomad FIN AF: 0.309

Gnomad MID AF: 0.232

Gnomad NFE AF: 0.307

Gnomad OTH AF: 0.267

GnomAD3 exomes AF: 0.317 AC: 79598 AN: 251088 Hom.: 13244 AF XY: 0.316 AC XY: 42841 AN XY: 135706

Gnomad AFR exome AF: 0.215

Gnomad AMR exome AF: 0.451

Gnomad ASJ exome AF: 0.275

Gnomad EAS exome AF: 0.280

Gnomad SAS exome AF: 0.300

Gnomad FIN exome AF: 0.300

Gnomad NFE exome AF: 0.310

Gnomad OTH exome AF: 0.296

GnomAD4 exome AF: 0.311 AC: 452188 AN: 1455638 Hom.: 71852 Cov.: 32 AF XY: 0.310 AC XY: 224783 AN XY: 724486

Gnomad4 AFR exome AF: 0.210

Gnomad4 AMR exome AF: 0.437

Gnomad4 ASJ exome AF: 0.279

Gnomad4 EAS exome AF: 0.253

Gnomad4 SAS exome AF: 0.304

Gnomad4 FIN exome AF: 0.303

Gnomad4 NFE exome AF: 0.313

Gnomad4 OTH exome AF: 0.300

GnomAD4 genome AF: 0.285 AC: 43251 AN: 151872 Hom.: 6360 Cov.: 32 AF XY: 0.288 AC XY: 21379 AN XY: 74200

Gnomad4 AFR AF: 0.216

Gnomad4 AMR AF: 0.358

Gnomad4 ASJ AF: 0.291

Gnomad4 EAS AF: 0.286

Gnomad4 SAS AF: 0.298

Gnomad4 FIN AF: 0.309

Gnomad4 NFE AF: 0.307

Gnomad4 OTH AF: 0.264

Alfa AF: 0.308 Hom.: 18256

Bravo AF: 0.290

TwinsUK AF: 0.324 AC: 1201

ALSPAC AF: 0.323 AC: 1243

ESP6500AA AF: 0.213 AC: 940

ESP6500EA AF: 0.305 AC: 2620

ExAC AF: 0.310 AC: 37694

Asia WGS AF: 0.277 AC: 966 AN: 3478

EpiCase AF: 0.315

EpiControl AF: 0.314

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.047	.;.;T;T
Eigen	Benign	-0.049
Eigen_PC	Benign	0.089
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D;D;D;D
MetaRNN	Benign	0.0049	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.7	.;.;.;L
MutationTaster	Benign	0.011	P;P;P;P;P
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.5	N;N;.;D
REVEL	Benign	0.092
Sift	Benign	0.078	T;T;.;T
Sift4G	Benign	0.24	T;T;T;T
Polyphen		0.0020, 0.0010	.;B;.;B
Vest4		0.20
MPC		0.077
ClinPred		0.062	T
GERP RS		3.3
Varity_R		0.16
gMVP		0.42

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: rs2286735; hg19: chr10-115389366; COSMIC: COSV63488541;