10-113589060-T-A

Variant names:

• chr10-113589060-T-A
• rs1845763069
• NM_198060.4:c.5108A>T

Variant summary

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

The NM_198060.4(NRAP):​c.5108A>T​(p.Glu1703Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,730 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NRAP NM_198060.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 0.549

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=0.16857624).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRAP	NM_198060.4	c.5108A>T	p.Glu1703Val	missense_variant	Exon 42 of 42	ENST00000359988.4	NP_932326.2
HABP2	NM_004132.5	c.*691T>A		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.5108A>T	p.Glu1703Val	missense_variant	Exon 42 of 42	1	NM_198060.4	ENSP00000353078.3
HABP2	ENST00000351270.4	c.*691T>A		3_prime_UTR_variant	Exon 13 of 13	1	NM_004132.5	ENSP00000277903.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461730 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727184

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

NRAP-related disorder Uncertain:1

Sep 13, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The NRAP c.5111A>T variant is predicted to result in the amino acid substitution p.Glu1704Val. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	10
DANN	Benign	0.97
DEOGEN2	Benign	0.031	.;.;T;T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.60	T;T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.17	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	.;.;.;L
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-2.1	N;N;.;N
REVEL	Benign	0.025
Sift	Uncertain	0.0090	D;D;.;D
Sift4G	Uncertain	0.035	D;D;D;D
Polyphen		0.19, 0.072	.;B;.;B
Vest4		0.27
MutPred		0.43		.;.;.;Loss of disorder (P = 0.0203);
MVP		0.33
MPC		0.083
ClinPred		0.34	T
GERP RS		3.1
Varity_R		0.12
gMVP		0.31

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: rs1845763069; hg19: chr10-115348819;