3-52455654-C-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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

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 Uncertain_significance. Variant got 0 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NISCH	NM_007184.4	c.13C>T	p.Arg5Cys	missense_variant	Exon 1 of 21	ENST00000345716.9	NP_009115.3
NISCH	NM_001276293.2	c.13C>T	p.Arg5Cys	missense_variant	Exon 1 of 13		NP_001263222.2
NISCH	NM_001276294.2	c.13C>T	p.Arg5Cys	missense_variant	Exon 1 of 14		NP_001263223.2
NISCH	XM_047447373.1	c.13C>T	p.Arg5Cys	missense_variant	Exon 1 of 18		XP_047303329.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NISCH	ENST00000345716.9	c.13C>T	p.Arg5Cys	missense_variant	Exon 1 of 21	1	NM_007184.4	ENSP00000339958.4
NISCH	ENST00000479054.5	c.13C>T	p.Arg5Cys	missense_variant	Exon 2 of 22	1		ENSP00000418232.1
NISCH	ENST00000488380.5	c.13C>T	p.Arg5Cys	missense_variant	Exon 1 of 13	1		ENSP00000417812.1
NISCH	ENST00000420808.2	c.13C>T	p.Arg5Cys	missense_variant	Exon 1 of 14	5		ENSP00000392484.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000164 AC: 2 AN: 121946 Hom.: 0 AF XY: 0.0000282 AC XY: 2 AN XY: 71026

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 SAS exome AF: 0.0000669

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000264

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000103

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000876 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;T;.;.
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.095	N
LIST_S2	Benign	0.83	.;T;T;T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.13	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.69	N;N;.;N
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.40	N;N;N;N
REVEL	Benign	0.084
Sift	Uncertain	0.0040	D;D;D;D
Sift4G	Uncertain	0.010	D;D;D;D
Polyphen		0.73	P;P;P;.
Vest4		0.25
MutPred		0.30		Loss of disorder (P = 0.0392);Loss of disorder (P = 0.0392);Loss of disorder (P = 0.0392);Loss of disorder (P = 0.0392);
MVP		0.068
MPC		0.85
ClinPred		0.46	T
GERP RS		0.76
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.17
gMVP		0.32

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

Publications

LitVar

Other links and lift over

dbSNP: rs758816689; hg19: chr3-52489670;