rs12241995

Positions:

• chr10-113597319-G-A
• chr10-113597319-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000359988.4(NRAP):​c.4333-135C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.258 in 635,982 control chromosomes in the GnomAD database, including 22,360 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (5097 hom., cov: 32)
  • Exomes 𝑓: 0.26 (17263 hom.)
• Consequence: NRAP ENST00000359988.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.278

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 10-113597319-G-A is Benign according to our data. Variant chr10-113597319-G-A is described in ClinVar as [Benign]. Clinvar id is 1294904.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.414 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NRAP	NM_198060.4	c.4333-135C>T		intron_variant		ENST00000359988.4	NP_932326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NRAP	ENST00000359988.4	c.4333-135C>T		intron_variant		1	NM_198060.4	ENSP00000353078	A1
NRAP	ENST00000360478.7	c.4228-135C>T		intron_variant		1		ENSP00000353666
NRAP	ENST00000369358.8	c.4333-135C>T		intron_variant		1		ENSP00000358365	P5
NRAP	ENST00000369360.7	c.4252-135C>T		intron_variant		5		ENSP00000358367

Frequencies

GnomAD3 genomes AF: 0.253 AC: 38455 AN: 151832 Hom.: 5087 Cov.: 32

Gnomad AFR AF: 0.258

Gnomad AMI AF: 0.332

Gnomad AMR AF: 0.253

Gnomad ASJ AF: 0.163

Gnomad EAS AF: 0.430

Gnomad SAS AF: 0.308

Gnomad FIN AF: 0.222

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.241

Gnomad OTH AF: 0.277

GnomAD4 exome AF: 0.259 AC: 125343 AN: 484032 Hom.: 17263 AF XY: 0.260 AC XY: 67306 AN XY: 259148

Gnomad4 AFR exome AF: 0.263

Gnomad4 AMR exome AF: 0.295

Gnomad4 ASJ exome AF: 0.170

Gnomad4 EAS exome AF: 0.421

Gnomad4 SAS exome AF: 0.298

Gnomad4 FIN exome AF: 0.216

Gnomad4 NFE exome AF: 0.241

Gnomad4 OTH exome AF: 0.257

GnomAD4 genome AF: 0.253 AC: 38481 AN: 151950 Hom.: 5097 Cov.: 32 AF XY: 0.254 AC XY: 18828 AN XY: 74268

Gnomad4 AFR AF: 0.258

Gnomad4 AMR AF: 0.253

Gnomad4 ASJ AF: 0.163

Gnomad4 EAS AF: 0.429

Gnomad4 SAS AF: 0.307

Gnomad4 FIN AF: 0.222

Gnomad4 NFE AF: 0.241

Gnomad4 OTH AF: 0.277

Alfa AF: 0.183 Hom.: 502

Bravo AF: 0.259

Asia WGS AF: 0.337 AC: 1170 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 14, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.7
DANN	Benign	0.17

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: rs12241995; hg19: chr10-115357078; COSMIC: COSV63489223;