rs3189030

Variant names:

• chr10-113634170-G-A
• rs3189030
• NM_198060.4:c.1469C>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.1469C>T​(p.Ser490Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.31 in 1,611,454 control chromosomes in the GnomAD database, including 80,769 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.27 (6059 hom., cov: 32)
  • Exomes 𝑓: 0.31 (74710 hom.)
• Consequence: NRAP NM_198060.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.49

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=9.263754E-4).
• BP6: Variant 10-113634170-G-A is Benign according to our data. Variant chr10-113634170-G-A is described in ClinVar as [Benign]. Clinvar id is 1263978.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.424 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRAP	NM_198060.4	c.1469C>T	p.Ser490Leu	missense_variant	Exon 15 of 42	ENST00000359988.4	NP_932326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NRAP	ENST00000359988.4	c.1469C>T	p.Ser490Leu	missense_variant	Exon 15 of 42	1	NM_198060.4	ENSP00000353078.3
NRAP	ENST00000369358.8	c.1469C>T	p.Ser490Leu	missense_variant	Exon 15 of 42	1		ENSP00000358365.4
NRAP	ENST00000360478.7	c.1364C>T	p.Ser455Leu	missense_variant	Exon 14 of 41	1		ENSP00000353666.3
NRAP	ENST00000369360.7	c.1364C>T	p.Ser455Leu	missense_variant	Exon 14 of 41	5		ENSP00000358367.3

Frequencies

GnomAD3 genomes AF: 0.268 AC: 40687 AN: 151894 Hom.: 6059 Cov.: 32

Gnomad AFR AF: 0.141

Gnomad AMI AF: 0.423

Gnomad AMR AF: 0.280

Gnomad ASJ AF: 0.185

Gnomad EAS AF: 0.440

Gnomad SAS AF: 0.346

Gnomad FIN AF: 0.329

Gnomad MID AF: 0.269

Gnomad NFE AF: 0.316

Gnomad OTH AF: 0.283

GnomAD3 exomes AF: 0.307 AC: 77221 AN: 251216 Hom.: 12622 AF XY: 0.309 AC XY: 41906 AN XY: 135776

Gnomad AFR exome AF: 0.134

Gnomad AMR exome AF: 0.298

Gnomad ASJ exome AF: 0.191

Gnomad EAS exome AF: 0.438

Gnomad SAS exome AF: 0.332

Gnomad FIN exome AF: 0.329

Gnomad NFE exome AF: 0.314

Gnomad OTH exome AF: 0.299

GnomAD4 exome AF: 0.314 AC: 458714 AN: 1459442 Hom.: 74710 Cov.: 32 AF XY: 0.315 AC XY: 228513 AN XY: 726154

Gnomad4 AFR exome AF: 0.130

Gnomad4 AMR exome AF: 0.304

Gnomad4 ASJ exome AF: 0.196

Gnomad4 EAS exome AF: 0.470

Gnomad4 SAS exome AF: 0.326

Gnomad4 FIN exome AF: 0.326

Gnomad4 NFE exome AF: 0.317

Gnomad4 OTH exome AF: 0.298

GnomAD4 genome AF: 0.268 AC: 40684 AN: 152012 Hom.: 6059 Cov.: 32 AF XY: 0.270 AC XY: 20080 AN XY: 74296

Gnomad4 AFR AF: 0.141

Gnomad4 AMR AF: 0.281

Gnomad4 ASJ AF: 0.185

Gnomad4 EAS AF: 0.439

Gnomad4 SAS AF: 0.344

Gnomad4 FIN AF: 0.329

Gnomad4 NFE AF: 0.316

Gnomad4 OTH AF: 0.284

Alfa AF: 0.302 Hom.: 17998

Bravo AF: 0.257

TwinsUK AF: 0.302 AC: 1121

ALSPAC AF: 0.318 AC: 1227

ESP6500AA AF: 0.139 AC: 614

ESP6500EA AF: 0.308 AC: 2652

ExAC AF: 0.306 AC: 37156

Asia WGS AF: 0.338 AC: 1174 AN: 3478

EpiCase AF: 0.301

EpiControl AF: 0.299

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 13, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 29874175) -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

NRAP-related disorder Benign:1

Oct 18, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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	0.13
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	18
DANN	Benign	0.95
DEOGEN2	Benign	0.11	.;.;T;T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.49
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.83	T;T;T;T
MetaRNN	Benign	0.00093	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.1	.;.;.;M
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.1	D;D;D;D
REVEL	Benign	0.071
Sift	Benign	0.097	T;T;T;T
Sift4G	Uncertain	0.034	D;D;D;D
Polyphen		0.083, 0.050	.;B;.;B
Vest4		0.086
MPC		0.070
ClinPred		0.011	T
GERP RS		3.3
Varity_R		0.087
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: rs3189030; hg19: chr10-115393929; COSMIC: COSV63489230;