rs6810027

Positions:

• chr3-52490558-C-A
• chr3-52490558-C-G
• chr3-52490558-C-T

Variant summary

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

The NM_007184.4(NISCH):​c.3614-147C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.953 in 1,124,192 control chromosomes in the GnomAD database, including 511,205 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 (70618 hom., cov: 33)
  • Exomes 𝑓: 0.95 (440587 hom.)
• Consequence: NISCH NM_007184.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.167

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=-0.87).
• 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	Protein	UniProt
NISCH	NM_007184.4	c.3614-147C>A		intron_variant		ENST00000345716.9	NP_009115.3
NISCH	XM_006712955.4	c.2096-147C>A		intron_variant			XP_006713018.1
NISCH	XM_047447373.1	c.3457-794C>A		intron_variant			XP_047303329.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NISCH	ENST00000345716.9	c.3614-147C>A		intron_variant		1	NM_007184.4	ENSP00000339958
NISCH	ENST00000479054.5	c.3614-147C>A		intron_variant		1		ENSP00000418232
NISCH	ENST00000467594.1	n.660-147C>A		intron_variant, non_coding_transcript_variant		2
NISCH	ENST00000489895.5	n.3863-147C>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.963 AC: 146482 AN: 152160 Hom.: 70558 Cov.: 33

Gnomad AFR AF: 0.990

Gnomad AMI AF: 0.933

Gnomad AMR AF: 0.946

Gnomad ASJ AF: 0.970

Gnomad EAS AF: 0.979

Gnomad SAS AF: 0.980

Gnomad FIN AF: 0.969

Gnomad MID AF: 0.962

Gnomad NFE AF: 0.947

Gnomad OTH AF: 0.957

GnomAD4 exome AF: 0.952 AC: 925250 AN: 971914 Hom.: 440587 AF XY: 0.952 AC XY: 468792 AN XY: 492210

Gnomad4 AFR exome AF: 0.990

Gnomad4 AMR exome AF: 0.959

Gnomad4 ASJ exome AF: 0.970

Gnomad4 EAS exome AF: 0.984

Gnomad4 SAS exome AF: 0.980

Gnomad4 FIN exome AF: 0.966

Gnomad4 NFE exome AF: 0.945

Gnomad4 OTH exome AF: 0.952

GnomAD4 genome AF: 0.963 AC: 146601 AN: 152278 Hom.: 70618 Cov.: 33 AF XY: 0.965 AC XY: 71806 AN XY: 74434

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: 0.969

Gnomad4 NFE AF: 0.947

Gnomad4 OTH AF: 0.957

Alfa AF: 0.960 Hom.: 12550

Bravo AF: 0.962

Asia WGS AF: 0.966 AC: 3357 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.52
DANN	Benign	0.60

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: rs6810027; hg19: chr3-52524574;