10-113588989-CCTT-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PM4_Supporting BP6_Very_Strong BS1 BS2

The NM_198060.4(NRAP):c.5176_5178del(p.Lys1726del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.00171 in 1,613,520 control chromosomes in the GnomAD database, including 37 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0085 (12 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (25 hom.)
• Consequence: NRAP NM_198060.4 inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.93

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 Benign. Variant got -15 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_198060.4. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 10-113588989-CCTT-C is Benign according to our data. Variant chr10-113588989-CCTT-C is described in ClinVar as [Likely_benign]. Clinvar id is 298931.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00847 (1289/152218) while in subpopulation AFR AF= 0.0288 (1195/41518). AF 95% confidence interval is 0.0274. There are 12 homozygotes in gnomad4. There are 596 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NRAP	NM_198060.4	c.5176_5178del	p.Lys1726del	inframe_deletion	42/42	ENST00000359988.4
HABP2	NM_004132.5	c.*627_*629del		3_prime_UTR_variant	13/13	ENST00000351270.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NRAP	ENST00000359988.4	c.5176_5178del	p.Lys1726del	inframe_deletion	42/42	1	NM_198060.4	A1
HABP2	ENST00000351270.4	c.*627_*629del		3_prime_UTR_variant	13/13	1	NM_004132.5	P1

Frequencies

GnomAD3 genomes AF: 0.00845 AC: 1286 AN: 152100 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.0288

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00412

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.00235 AC: 585 AN: 249242 Hom.: 9 AF XY: 0.00168 AC XY: 226 AN XY: 134890

Gnomad AFR exome AF: 0.0311

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.000693

Gnomad NFE exome AF: 0.000152

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.00101 AC: 1478 AN: 1461302 Hom.: 25 AF XY: 0.000876 AC XY: 637 AN XY: 727000

Gnomad4 AFR exome AF: 0.0306

Gnomad4 AMR exome AF: 0.00174

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000705

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.000636

Gnomad4 NFE exome AF: 0.000154

Gnomad4 OTH exome AF: 0.00192

GnomAD4 genome AF: 0.00847 AC: 1289 AN: 152218 Hom.: 12 Cov.: 32 AF XY: 0.00801 AC XY: 596 AN XY: 74418

Gnomad4 AFR AF: 0.0288

Gnomad4 AMR AF: 0.00405

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00805

Alfa AF: 0.00109 Hom.: 1

Bravo AF: 0.00980

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

NRAP-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 01, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Factor VII Marburg I Variant Thrombophilia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

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: rs11575787; hg19: chr10-115348748;