NM_007184.4:c.13C>T

Variant names:

• chr3-52455654-C-T
• rs758816689
• NM_007184.4:c.13C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_007184.4(NISCH):​c.13C>T​(p.Arg5Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000168 in 1,192,664 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R5G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000017 (0 hom.)
• Consequence: NISCH NM_007184.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.167
• Publications: 5 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1327307).

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.13C>T	p.Arg5Cys	missense	Exon 1 of 21	NP_009115.3	Q9Y2I1-1
	NISCH	NM_001276293.2		c.13C>T	p.Arg5Cys	missense	Exon 1 of 13	NP_001263222.2	C9J715
	NISCH	NM_001276294.2		c.13C>T	p.Arg5Cys	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.13C>T	p.Arg5Cys	missense	Exon 1 of 21	ENSP00000339958.4	Q9Y2I1-1
	NISCH	ENST00000479054.5	TSL:1	c.13C>T	p.Arg5Cys	missense	Exon 2 of 22	ENSP00000418232.1	Q9Y2I1-1
	NISCH	ENST00000488380.5	TSL:1	c.13C>T	p.Arg5Cys	missense	Exon 1 of 13	ENSP00000417812.1	C9J715

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000164 AC: 2 AN: 121946 AF XY: 0.0000282

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000162

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000168 AC: 2 AN: 1192664 Hom.: 0 Cov.: 31 AF XY: 0.00000346 AC XY: 2 AN XY: 577832

African (AFR) AF: 0.00 AC: 0 AN: 25040

American (AMR) AF: 0.00 AC: 0 AN: 17996

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17960

East Asian (EAS) AF: 0.00 AC: 0 AN: 30394

South Asian (SAS) AF: 0.0000264 AC: 1 AN: 37834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4754

European-Non Finnish (NFE) AF: 0.00000103 AC: 1 AN: 971782

Other (OTH) AF: 0.00 AC: 0 AN: 47284

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000876 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.045	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.095	N
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.17
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.40	N
REVEL	Benign	0.084
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.010	D
Polyphen		0.73	P
Vest4		0.25
MutPred		0.30		Loss of disorder (P = 0.0392)
MVP		0.068
MPC		0.85
ClinPred		0.46	T
GERP RS		0.76
PromoterAI		0.022	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.17
gMVP		0.32
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs758816689; hg19: chr3-52489670;