chr10-113590838-G-C

Position:

• chr10-113590838-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000359988.4(NRAP):​c.4696C>G​(p.Arg1566Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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 Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NRAP ENST00000359988.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.61

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 Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NRAP	NM_198060.4	c.4696C>G	p.Arg1566Gly	missense_variant	40/42	ENST00000359988.4	NP_932326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NRAP	ENST00000359988.4	c.4696C>G	p.Arg1566Gly	missense_variant	40/42	1	NM_198060.4	ENSP00000353078	A1
NRAP	ENST00000369358.8	c.4696C>G	p.Arg1566Gly	missense_variant	40/42	1		ENSP00000358365	P5
NRAP	ENST00000360478.7	c.4591C>G	p.Arg1531Gly	missense_variant	39/41	1		ENSP00000353666
NRAP	ENST00000369360.7	c.4615C>G	p.Arg1539Gly	missense_variant	39/41	5		ENSP00000358367

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 45

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.0025	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	.;.;T;T
Eigen	Benign	0.16
Eigen_PC	Benign	0.18
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D;D;D
M_CAP	Benign	0.022	T
MetaRNN	Uncertain	0.63	D;D;D;D
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.7	.;.;.;M
MutationTaster	Benign	0.17	P;P;P;P;P
PrimateAI	Benign	0.25	T
PROVEAN	Pathogenic	-5.8	D;D;.;D
REVEL	Benign	0.14
Sift	Uncertain	0.0060	D;D;.;D
Sift4G	Uncertain	0.020	D;D;D;D
Polyphen		0.61, 0.47	.;P;.;P
Vest4		0.59
MutPred		0.42		.;.;Loss of MoRF binding (P = 0.0369);Loss of MoRF binding (P = 0.0369);
MVP		0.53
MPC		0.17
ClinPred		0.98	D
GERP RS		3.8
Varity_R		0.51
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1885434; hg19: chr10-115350597;