NM_198060.4:c.1469C>T

Variant names:

• chr10-113634170-G-A
• rs3189030
• NM_198060.4:c.1469C>T

Variant summary

Our verdict is Benign. The variant received -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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S490S) has been classified as Benign.

• 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:4
• Conservation: PhyloP100: 2.49
• Publications: 32 publications found

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 Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AR Classification: STRONG Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198060.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRAP	NM_198060.4	MANE Select	c.1469C>T	p.Ser490Leu	missense	Exon 15 of 42	NP_932326.2
	NRAP	NM_001261463.2		c.1469C>T	p.Ser490Leu	missense	Exon 15 of 42	NP_001248392.1	A0A0A0MRM2
	NRAP	NM_006175.5		c.1364C>T	p.Ser455Leu	missense	Exon 14 of 41	NP_006166.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRAP	ENST00000359988.4	TSL:1 MANE Select	c.1469C>T	p.Ser490Leu	missense	Exon 15 of 42	ENSP00000353078.3	Q86VF7-1
	NRAP	ENST00000369358.8	TSL:1	c.1469C>T	p.Ser490Leu	missense	Exon 15 of 42	ENSP00000358365.4	A0A0A0MRM2
	NRAP	ENST00000360478.7	TSL:1	c.1364C>T	p.Ser455Leu	missense	Exon 14 of 41	ENSP00000353666.3	Q86VF7-4

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

GnomAD2 exomes AF: 0.307 AC: 77221 AN: 251216 AF XY: 0.309

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 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

African (AFR) AF: 0.130 AC: 4348 AN: 33456

American (AMR) AF: 0.304 AC: 13579 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.196 AC: 5112 AN: 26116

East Asian (EAS) AF: 0.470 AC: 18667 AN: 39682

South Asian (SAS) AF: 0.326 AC: 28116 AN: 86178

European-Finnish (FIN) AF: 0.326 AC: 17412 AN: 53408

Middle Eastern (MID) AF: 0.290 AC: 1671 AN: 5766

European-Non Finnish (NFE) AF: 0.317 AC: 351815 AN: 1109804

Other (OTH) AF: 0.298 AC: 17994 AN: 60326

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

African (AFR) AF: 0.141 AC: 5833 AN: 41502

American (AMR) AF: 0.281 AC: 4282 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.185 AC: 640 AN: 3466

East Asian (EAS) AF: 0.439 AC: 2263 AN: 5154

South Asian (SAS) AF: 0.344 AC: 1658 AN: 4816

European-Finnish (FIN) AF: 0.329 AC: 3465 AN: 10534

Middle Eastern (MID) AF: 0.262 AC: 77 AN: 294

European-Non Finnish (NFE) AF: 0.316 AC: 21482 AN: 67968

Other (OTH) AF: 0.284 AC: 598 AN: 2104

Alfa AF: 0.295 Hom.: 24305

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	1	NRAP-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.49
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.00093	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		2.5
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.071
Sift	Benign	0.097	T
Sift4G	Uncertain	0.034	D
Polyphen		0.083	B
Vest4		0.086
MPC		0.070
ClinPred		0.011	T
GERP RS		3.3
Varity_R		0.087
gMVP		0.54
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3189030; hg19: chr10-115393929; COSMIC: COSV63489230;