10-113590838-G-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_198060.4(NRAP):​c.4696C>A​(p.Arg1566Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,868 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1566C) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NRAP NM_198060.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.61
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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>A	p.Arg1566Ser	missense	Exon 40 of 42	NP_932326.2
	NRAP	NM_001261463.2		c.4696C>A	p.Arg1566Ser	missense	Exon 40 of 42	NP_001248392.1	A0A0A0MRM2
	NRAP	NM_006175.5		c.4591C>A	p.Arg1531Ser	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>A	p.Arg1566Ser	missense	Exon 40 of 42	ENSP00000353078.3	Q86VF7-1
	NRAP	ENST00000369358.8	TSL:1	c.4696C>A	p.Arg1566Ser	missense	Exon 40 of 42	ENSP00000358365.4	A0A0A0MRM2
	NRAP	ENST00000360478.7	TSL:1	c.4591C>A	p.Arg1531Ser	missense	Exon 39 of 41	ENSP00000353666.3	Q86VF7-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461868 Hom.: 0 Cov.: 45 AF XY: 0.00 AC XY: 0 AN XY: 727238

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.032	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Benign	0.022
Eigen_PC	Benign	0.073
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		3.6
PrimateAI	Benign	0.25	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Benign	0.15
Sift	Benign	0.059	T
Sift4G	Uncertain	0.025	D
Polyphen		0.61	P
Vest4		0.51
MutPred		0.38		Loss of MoRF binding (P = 0.0442)
MVP		0.53
MPC		0.12
ClinPred		0.98	D
GERP RS		3.8
Varity_R		0.45
gMVP		0.60
Mutation Taster		=88/12	polymorphism

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;