3-52484770-T-C

Position:

• chr3-52484770-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_007184.4(NISCH):​c.1653+133T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.955 in 933,584 control chromosomes in the GnomAD database, including 426,173 homozygotes. 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: 𝑓 0.96 (70421 hom., cov: 27)
  • Exomes 𝑓: 0.95 (355752 hom.)
• Consequence: NISCH NM_007184.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.836

Genes affected

NISCH (HGNC:18006): (nischarin) This gene encodes a nonadrenergic imidazoline-1 receptor protein that localizes to the cytosol and anchors to the inner layer of the plasma membrane. The orthologous mouse protein has been shown to influence cytoskeletal organization and cell migration by binding to alpha-5-beta-1 integrin. In humans, this protein has been shown to bind to the adapter insulin receptor substrate 4 (IRS4) to mediate translocation of alpha-5 integrin from the cell membrane to endosomes. Expression of this protein was reduced in human breast cancers while its overexpression reduced tumor growth and metastasis; possibly by limiting the expression of alpha-5 integrin. In human cardiac tissue, this gene was found to affect cell growth and death while in neural tissue it affected neuronal growth and differentiation. Alternative splicing results in multiple transcript variants encoding differerent isoforms. Some isoforms lack the expected C-terminal domains of a functional imidazoline receptor. [provided by RefSeq, Jan 2013]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.982 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NISCH	NM_007184.4	c.1653+133T>C		intron_variant		ENST00000345716.9
NISCH	XM_006712955.4	c.135+133T>C		intron_variant
NISCH	XM_047447373.1	c.1653+133T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NISCH	ENST00000345716.9	c.1653+133T>C		intron_variant		1	NM_007184.4

Frequencies

GnomAD3 genomes AF: 0.963 AC: 146072 AN: 151734 Hom.: 70361 Cov.: 27

Gnomad AFR AF: 0.990

Gnomad AMI AF: 0.931

Gnomad AMR AF: 0.946

Gnomad ASJ AF: 0.970

Gnomad EAS AF: 0.979

Gnomad SAS AF: 0.980

Gnomad FIN AF: 0.970

Gnomad MID AF: 0.962

Gnomad NFE AF: 0.947

Gnomad OTH AF: 0.957

GnomAD4 exome AF: 0.954 AC: 745617 AN: 781732 Hom.: 355752 AF XY: 0.954 AC XY: 383194 AN XY: 401482

Gnomad4 AFR exome AF: 0.990

Gnomad4 AMR exome AF: 0.960

Gnomad4 ASJ exome AF: 0.971

Gnomad4 EAS exome AF: 0.985

Gnomad4 SAS exome AF: 0.980

Gnomad4 FIN exome AF: 0.965

Gnomad4 NFE exome AF: 0.946

Gnomad4 OTH exome AF: 0.952

GnomAD4 genome AF: 0.963 AC: 146191 AN: 151852 Hom.: 70421 Cov.: 27 AF XY: 0.965 AC XY: 71562 AN XY: 74184

Gnomad4 AFR AF: 0.990

Gnomad4 AMR AF: 0.946

Gnomad4 ASJ AF: 0.970

Gnomad4 EAS AF: 0.979

Gnomad4 SAS AF: 0.980

Gnomad4 FIN AF: 0.970

Gnomad4 NFE AF: 0.947

Gnomad4 OTH AF: 0.956

Alfa AF: 0.960 Hom.: 8717

Bravo AF: 0.962

Asia WGS AF: 0.966 AC: 3360 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.4
DANN	Benign	0.61

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: rs4687619; hg19: chr3-52518786;