NM_198060.4:c.2021C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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 (★★).

Frequency

Genomes: 𝑓 0.28 ( 6360 hom., cov: 32)

Exomes 𝑓: 0.31 ( 71852 hom. )

Consequence

NRAP
NM_198060.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 6.92

Publications

21 publications found

Variant links:

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]

NRAP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
NRAP	NM_198060.4 link	c.2021C>T	p.Ala674Val	missense_variant	Exon 19 of 42	ENST00000359988.4	NP_932326.2	Q86VF7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NRAP	ENST00000359988.4 link	c.2021C>T	p.Ala674Val	missense_variant	Exon 19 of 42	1	NM_198060.4	ENSP00000353078.3	Q86VF7-1
NRAP	ENST00000369358.8 link	c.2021C>T	p.Ala674Val	missense_variant	Exon 19 of 42	1		ENSP00000358365.4	A0A0A0MRM2
NRAP	ENST00000360478.7 link	c.1916C>T	p.Ala639Val	missense_variant	Exon 18 of 41	1		ENSP00000353666.3	Q86VF7-4
NRAP	ENST00000369360.7 link	c.1940C>T	p.Ala647Val	missense_variant	Exon 18 of 41	5		ENSP00000358367.3	Q86VF7-3

Frequencies

GnomAD3 genomes

AF:

0.285

AC:

43185

AN:

151752

Hom.:

6338

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.317

AC:

79598

AN:

251088

AF XY:

0.316

show subpopulations

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 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.:

AF XY:

0.310

AC XY:

224783

AN XY:

724486

show subpopulations

African (AFR)

AF:

0.210

AC:

7002

AN:

33386

American (AMR)

AF:

0.437

AC:

19557

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.279

AC:

7294

AN:

26114

East Asian (EAS)

AF:

0.253

AC:

10039

AN:

39666

South Asian (SAS)

AF:

0.304

AC:

26179

AN:

86126

European-Finnish (FIN)

AF:

0.303

AC:

16195

AN:

53370

Middle Eastern (MID)

AF:

0.254

AC:

1441

AN:

5670

European-Non Finnish (NFE)

AF:

0.313

AC:

346446

AN:

1106402

Other (OTH)

AF:

0.300

AC:

18035

AN:

60190

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

13839

27679

41518

55358

69197

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11334

22668

34002

45336

56670

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.285

AC:

43251

AN:

151872

Hom.:

6360

Cov.:

AF XY:

0.288

AC XY:

21379

AN XY:

74200

show subpopulations

African (AFR)

AF:

0.216

AC:

8953

AN:

41484

American (AMR)

AF:

0.358

AC:

5475

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.291

AC:

1009

AN:

3466

East Asian (EAS)

AF:

0.286

AC:

1469

AN:

5140

South Asian (SAS)

AF:

0.298

AC:

1434

AN:

4808

European-Finnish (FIN)

AF:

0.309

AC:

3257

AN:

10530

Middle Eastern (MID)

AF:

0.243

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.307

AC:

20828

AN:

67860

Other (OTH)

AF:

0.264

AC:

557

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1584

3168

4753

6337

7921

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

460

920

1380

1840

2300

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.305

Hom.:

24497

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:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

May 04, 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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.047

.;.;T;T

Eigen

Benign

-0.049

Eigen_PC

Benign

0.089

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.87

D;D;D;D

MetaRNN

Benign

0.0049

T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.7

.;.;.;L

PhyloP100

6.9

PrimateAI

Uncertain

0.53

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

GERP RS

3.3

Varity_R

0.16

gMVP

0.42

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over