NM_198060.4:c.5167A>G

Variant names:

• chr10-113589001-T-C
• rs1003369026
• NM_198060.4:c.5167A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_198060.4(NRAP):​c.5167A>G​(p.Lys1723Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NRAP NM_198060.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.90

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]

HABP2 (HGNC:4798): (hyaluronan binding protein 2) This gene encodes a member of the peptidase S1 family of serine proteases. The encoded preproprotein is secreted by hepatocytes and proteolytically processed to generate heavy and light chains that form the mature heterodimer. Further autoproteolysis leads to smaller, inactive peptides. This extracellular protease binds hyaluronic acid and may play a role in the coagulation and fibrinolysis systems. Mutations in this gene are associated with nonmedullary thyroid cancer and susceptibility to venous thromboembolism. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25262645).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRAP	NM_198060.4	c.5167A>G	p.Lys1723Glu	missense_variant	Exon 42 of 42	ENST00000359988.4	NP_932326.2
HABP2	NM_004132.5	c.*632T>C		3_prime_UTR_variant	Exon 13 of 13	ENST00000351270.4	NP_004123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NRAP	ENST00000359988.4	c.5167A>G	p.Lys1723Glu	missense_variant	Exon 42 of 42	1	NM_198060.4	ENSP00000353078.3
HABP2	ENST00000351270.4	c.*632T>C		3_prime_UTR_variant	Exon 13 of 13	1	NM_004132.5	ENSP00000277903.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Aug 16, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5167A>G (p.K1723E) alteration is located in exon 42 (coding exon 42) of the NRAP gene. This alteration results from a A to G substitution at nucleotide position 5167, causing the lysine (K) at amino acid position 1723 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.026	.;.;T;T
Eigen	Benign	-0.048
Eigen_PC	Benign	0.044
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.83	T;T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.25	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	.;.;.;L
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.2	N;N;.;N
REVEL	Benign	0.093
Sift	Uncertain	0.010	D;D;.;D
Sift4G	Uncertain	0.010	D;D;D;D
Polyphen		0.39, 0.27	.;B;.;B
Vest4		0.40
MutPred		0.49		.;.;.;Loss of MoRF binding (P = 7e-04);
MVP		0.41
MPC		0.12
ClinPred		0.88	D
GERP RS		4.5
Varity_R		0.18
gMVP		0.74

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: rs1003369026; hg19: chr10-115348760;