rs1885434

Variant names:

• chr10-113590838-G-A
• rs1885434
• NM_198060.4:c.4696C>T

Your query was ambiguous. Multiple possible variants found:

• chr10-113590838-G-A
• chr10-113590838-G-C
• chr10-113590838-G-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.37 (10708 hom., cov: 32)
  • Exomes 𝑓: 0.35 (88031 hom.)
• Consequence: NRAP NM_198060.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.61
• Publications: 28 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0027224123).
• BP6: Variant 10-113590838-G-A is Benign according to our data. Variant chr10-113590838-G-A is described in ClinVar as Benign. ClinVar VariationId is 3894686.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.453 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.4696C>T	p.Arg1566Cys	missense	Exon 40 of 42	NP_932326.2
	NRAP	NM_001261463.2		c.4696C>T	p.Arg1566Cys	missense	Exon 40 of 42	NP_001248392.1	A0A0A0MRM2
	NRAP	NM_006175.5		c.4591C>T	p.Arg1531Cys	missense	Exon 39 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.4696C>T	p.Arg1566Cys	missense	Exon 40 of 42	ENSP00000353078.3	Q86VF7-1
	NRAP	ENST00000369358.8	TSL:1	c.4696C>T	p.Arg1566Cys	missense	Exon 40 of 42	ENSP00000358365.4	A0A0A0MRM2
	NRAP	ENST00000360478.7	TSL:1	c.4591C>T	p.Arg1531Cys	missense	Exon 39 of 41	ENSP00000353666.3	Q86VF7-4

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

GnomAD2 exomes AF: 0.359 AC: 89922 AN: 250634 AF XY: 0.352

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 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

African (AFR) AF: 0.414 AC: 13851 AN: 33468

American (AMR) AF: 0.488 AC: 21809 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.345 AC: 9025 AN: 26136

East Asian (EAS) AF: 0.314 AC: 12457 AN: 39700

South Asian (SAS) AF: 0.320 AC: 27622 AN: 86252

European-Finnish (FIN) AF: 0.301 AC: 16101 AN: 53410

Middle Eastern (MID) AF: 0.332 AC: 1916 AN: 5768

European-Non Finnish (NFE) AF: 0.342 AC: 380744 AN: 1111818

Other (OTH) AF: 0.345 AC: 20833 AN: 60392

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

African (AFR) AF: 0.416 AC: 17262 AN: 41448

American (AMR) AF: 0.462 AC: 7055 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.340 AC: 1178 AN: 3466

East Asian (EAS) AF: 0.319 AC: 1650 AN: 5166

South Asian (SAS) AF: 0.320 AC: 1540 AN: 4814

European-Finnish (FIN) AF: 0.294 AC: 3110 AN: 10582

Middle Eastern (MID) AF: 0.330 AC: 97 AN: 294

European-Non Finnish (NFE) AF: 0.343 AC: 23288 AN: 67978

Other (OTH) AF: 0.363 AC: 766 AN: 2112

Alfa AF: 0.352 Hom.: 33093

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.023
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		3.6
PrimateAI	Benign	0.27	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Benign	0.11
Sift	Benign	0.039	D
Sift4G	Uncertain	0.015	D
Polyphen		0.024	B
Vest4		0.30
MPC		0.097
ClinPred		0.077	T
GERP RS		3.8
Varity_R		0.23
gMVP		0.54
Mutation Taster		=90/10	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: rs1885434; hg19: chr10-115350597; COSMIC: COSV63488229; COSMIC: COSV63488229;