3-52455691-A-T

Variant names:

• chr3-52455691-A-T
• rs1159704460
• NM_007184.4:c.50A>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_007184.4(NISCH):​c.50A>T​(p.Lys17Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000165 in 1,213,066 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: not found (cov: 31)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: NISCH NM_007184.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.01
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28204012).

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.50A>T	p.Lys17Met	missense	Exon 1 of 21	NP_009115.3	Q9Y2I1-1
	NISCH	NM_001276293.2		c.50A>T	p.Lys17Met	missense	Exon 1 of 13	NP_001263222.2	C9J715
	NISCH	NM_001276294.2		c.50A>T	p.Lys17Met	missense	Exon 1 of 14	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.50A>T	p.Lys17Met	missense	Exon 1 of 21	ENSP00000339958.4	Q9Y2I1-1
	NISCH	ENST00000479054.5	TSL:1	c.50A>T	p.Lys17Met	missense	Exon 2 of 22	ENSP00000418232.1	Q9Y2I1-1
	NISCH	ENST00000488380.5	TSL:1	c.50A>T	p.Lys17Met	missense	Exon 1 of 13	ENSP00000417812.1	C9J715

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000165 AC: 2 AN: 1213066 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 590108

African (AFR) AF: 0.00 AC: 0 AN: 25208

American (AMR) AF: 0.000106 AC: 2 AN: 18930

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18786

East Asian (EAS) AF: 0.00 AC: 0 AN: 30628

South Asian (SAS) AF: 0.00 AC: 0 AN: 43336

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42252

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4828

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 981038

Other (OTH) AF: 0.00 AC: 0 AN: 48060

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		1.0
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.15
Sift	Uncertain	0.0060	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.50
MutPred		0.45		Loss of ubiquitination at K17 (P = 0.0087)
MVP		0.15
MPC		1.5
ClinPred		0.94	D
GERP RS		4.9
PromoterAI		0.044	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.35
Mutation Taster		=78/22	polymorphism

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: rs1159704460; hg19: chr3-52489707;