10-113597319-G-T

Variant names:

• chr10-113597319-G-T
• rs12241995
• NM_198060.4:c.4333-135C>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.4333-135C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000619 in 484,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: NRAP NM_198060.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.278
• Publications: 2 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]

NRAP Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AR Classification: STRONG Submitted by: ClinGen

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=-0.84).

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.4333-135C>A		intron	N/A	NP_932326.2
	NRAP	NM_001261463.2		c.4333-135C>A		intron	N/A	NP_001248392.1	A0A0A0MRM2
	NRAP	NM_006175.5		c.4228-135C>A		intron	N/A	NP_006166.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRAP	ENST00000359988.4	TSL:1 MANE Select	c.4333-135C>A		intron	N/A	ENSP00000353078.3	Q86VF7-1
	NRAP	ENST00000369358.8	TSL:1	c.4333-135C>A		intron	N/A	ENSP00000358365.4	A0A0A0MRM2
	NRAP	ENST00000360478.7	TSL:1	c.4228-135C>A		intron	N/A	ENSP00000353666.3	Q86VF7-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000619 AC: 3 AN: 484844 Hom.: 0 AF XY: 0.00000385 AC XY: 1 AN XY: 259550

African (AFR) AF: 0.00 AC: 0 AN: 13916

American (AMR) AF: 0.00 AC: 0 AN: 25696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14374

East Asian (EAS) AF: 0.00 AC: 0 AN: 31668

South Asian (SAS) AF: 0.00 AC: 0 AN: 50510

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36316

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3542

European-Non Finnish (NFE) AF: 0.0000106 AC: 3 AN: 281936

Other (OTH) AF: 0.00 AC: 0 AN: 26886

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 523

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	3.3
DANN	Benign	0.31
PhyloP100		0.28

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: rs12241995; hg19: chr10-115357078;