10-113588896-C-T

Variant names:

• chr10-113588896-C-T
• rs751515984
• NM_198060.4:c.*79G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_198060.4(NRAP):​c.*79G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 1,133,078 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: NRAP NM_198060.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.798
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198060.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRAP	NM_198060.4	MANE Select	c.*79G>A		3_prime_UTR	Exon 42 of 42	NP_932326.2
	HABP2	NM_004132.5	MANE Select	c.*527C>T		3_prime_UTR	Exon 13 of 13	NP_004123.1	Q14520-1
	NRAP	NM_001261463.2		c.*79G>A		3_prime_UTR	Exon 42 of 42	NP_001248392.1	A0A0A0MRM2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRAP	ENST00000359988.4	TSL:1 MANE Select	c.*79G>A		3_prime_UTR	Exon 42 of 42	ENSP00000353078.3	Q86VF7-1
	HABP2	ENST00000351270.4	TSL:1 MANE Select	c.*527C>T		3_prime_UTR	Exon 13 of 13	ENSP00000277903.4	Q14520-1
	NRAP	ENST00000369358.8	TSL:1	c.*79G>A		3_prime_UTR	Exon 42 of 42	ENSP00000358365.4	A0A0A0MRM2

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152088 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000143 AC: 14 AN: 980990 Hom.: 0 Cov.: 13 AF XY: 0.0000159 AC XY: 8 AN XY: 503700

African (AFR) AF: 0.0000419 AC: 1 AN: 23840

American (AMR) AF: 0.00 AC: 0 AN: 38954

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20906

East Asian (EAS) AF: 0.00 AC: 0 AN: 37286

South Asian (SAS) AF: 0.0000283 AC: 2 AN: 70588

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52058

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4700

European-Non Finnish (NFE) AF: 0.0000160 AC: 11 AN: 688448

Other (OTH) AF: 0.00 AC: 0 AN: 44210

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152088 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74264

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41408

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2088

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Factor VII Marburg I Variant Thrombophilia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.4
DANN	Benign	0.59
PhyloP100		-0.80

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

Other links and lift over

dbSNP: rs751515984; hg19: chr10-115348655;