3-52472475-A-G

Variant names:

• chr3-52472475-A-G
• rs6445486
• NM_007184.4:c.669+77A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_007184.4(NISCH):​c.669+77A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.954 in 1,285,430 control chromosomes in the GnomAD database, including 585,395 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 (70681 hom., cov: 34)
  • Exomes 𝑓: 0.95 (514714 hom.)
• Consequence: NISCH NM_007184.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.399
• Publications: 14 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.982 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007184.4. 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
	NISCH	NM_007184.4	MANE Select	c.669+77A>G		intron	N/A	NP_009115.3	Q9Y2I1-1
	NISCH	NM_001276293.2		c.669+77A>G		intron	N/A	NP_001263222.2	C9J715
	NISCH	NM_001276294.2		c.669+77A>G		intron	N/A	NP_001263223.2	Q9Y2I1-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NISCH	ENST00000345716.9	TSL:1 MANE Select	c.669+77A>G		intron	N/A	ENSP00000339958.4	Q9Y2I1-1
	NISCH	ENST00000479054.5	TSL:1	c.669+77A>G		intron	N/A	ENSP00000418232.1	Q9Y2I1-1
	NISCH	ENST00000488380.5	TSL:1	c.669+77A>G		intron	N/A	ENSP00000417812.1	C9J715

Frequencies

GnomAD3 genomes AF: 0.963 AC: 146583 AN: 152234 Hom.: 70621 Cov.: 34

Gnomad AFR AF: 0.990

Gnomad AMI AF: 0.931

Gnomad AMR AF: 0.949

Gnomad ASJ AF: 0.970

Gnomad EAS AF: 0.979

Gnomad SAS AF: 0.979

Gnomad FIN AF: 0.969

Gnomad MID AF: 0.962

Gnomad NFE AF: 0.947

Gnomad OTH AF: 0.958

GnomAD4 exome AF: 0.953 AC: 1079804 AN: 1133078 Hom.: 514714 AF XY: 0.953 AC XY: 550277 AN XY: 577144

African (AFR) AF: 0.990 AC: 26898 AN: 27176

American (AMR) AF: 0.962 AC: 41909 AN: 43584

Ashkenazi Jewish (ASJ) AF: 0.971 AC: 23030 AN: 23730

East Asian (EAS) AF: 0.984 AC: 37444 AN: 38046

South Asian (SAS) AF: 0.980 AC: 77736 AN: 79352

European-Finnish (FIN) AF: 0.966 AC: 46159 AN: 47796

Middle Eastern (MID) AF: 0.962 AC: 4476 AN: 4654

European-Non Finnish (NFE) AF: 0.946 AC: 774862 AN: 819100

Other (OTH) AF: 0.953 AC: 47290 AN: 49640

GnomAD4 genome AF: 0.963 AC: 146702 AN: 152352 Hom.: 70681 Cov.: 34 AF XY: 0.965 AC XY: 71890 AN XY: 74498

African (AFR) AF: 0.990 AC: 41160 AN: 41584

American (AMR) AF: 0.949 AC: 14514 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.970 AC: 3368 AN: 3472

East Asian (EAS) AF: 0.979 AC: 5078 AN: 5188

South Asian (SAS) AF: 0.979 AC: 4733 AN: 4834

European-Finnish (FIN) AF: 0.969 AC: 10289 AN: 10614

Middle Eastern (MID) AF: 0.959 AC: 282 AN: 294

European-Non Finnish (NFE) AF: 0.947 AC: 64405 AN: 68040

Other (OTH) AF: 0.957 AC: 2024 AN: 2114

Alfa AF: 0.953 Hom.: 6342

Bravo AF: 0.962

Asia WGS AF: 0.966 AC: 3359 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	4.2
DANN	Benign	0.31
PhyloP100		0.40
Mutation Taster		=100/0	polymorphism (auto)

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: rs6445486; hg19: chr3-52506491;