chr3-52457855-C-G

Position:

• chr3-52457855-C-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_007184.4(NISCH):​c.106C>G​(p.Gln36Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000363 in 1,459,290 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: 33)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: NISCH NM_007184.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.24

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12114066).
• BS2: High AC in GnomAdExome4 at 53 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NISCH	NM_007184.4	c.106C>G	p.Gln36Glu	missense_variant	2/21	ENST00000345716.9	NP_009115.3
NISCH	NM_001276293.2	c.106C>G	p.Gln36Glu	missense_variant	2/13		NP_001263222.2
NISCH	NM_001276294.2	c.106C>G	p.Gln36Glu	missense_variant	2/14		NP_001263223.2
NISCH	XM_047447373.1	c.106C>G	p.Gln36Glu	missense_variant	2/18		XP_047303329.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NISCH	ENST00000345716.9	c.106C>G	p.Gln36Glu	missense_variant	2/21	1	NM_007184.4	ENSP00000339958.4
NISCH	ENST00000479054.5	c.106C>G	p.Gln36Glu	missense_variant	3/22	1		ENSP00000418232.1
NISCH	ENST00000488380.5	c.106C>G	p.Gln36Glu	missense_variant	2/13	1		ENSP00000417812.1
NISCH	ENST00000420808.2	c.106C>G	p.Gln36Glu	missense_variant	2/14	5		ENSP00000392484.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000363 AC: 53 AN: 1459290 Hom.: 0 Cov.: 30 AF XY: 0.0000400 AC XY: 29 AN XY: 725510

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000468

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 19, 2024

The c.106C>G (p.Q36E) alteration is located in exon 2 (coding exon 2) of the NISCH gene. This alteration results from a C to G substitution at nucleotide position 106, causing the glutamine (Q) at amino acid position 36 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	20
DANN	Benign	0.92
DEOGEN2	Benign	0.068	T;T;.;.
Eigen	Benign	-0.20
Eigen_PC	Benign	0.075
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.90	.;D;D;D
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.12	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.57	N;N;.;N
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.63	N;N;N;N
REVEL	Benign	0.061
Sift	Benign	0.29	T;T;T;T
Sift4G	Benign	0.35	T;T;T;T
Polyphen		0.065	B;B;B;.
Vest4		0.32
MVP		0.12
MPC		0.46
ClinPred		0.67	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.51
gMVP		0.29

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: rs373680961; hg19: chr3-52491871;