3-52478251-A-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2 BP4_Moderate

The NM_007184.4(NISCH):c.1142A>G(p.Asn381Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: NISCH NM_007184.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.46

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 -1 ACMG points.

• PP2: Missense variant where missense usually causes diseases, NISCH
• BP4: Computational evidence support a benign effect (MetaRNN=0.25627488).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NISCH	NM_007184.4	c.1142A>G	p.Asn381Ser	missense_variant	10/21	ENST00000345716.9
NISCH	NM_001276293.2	c.1142A>G	p.Asn381Ser	missense_variant	10/13
NISCH	NM_001276294.2	c.1142A>G	p.Asn381Ser	missense_variant	10/14
NISCH	XM_047447373.1	c.1142A>G	p.Asn381Ser	missense_variant	10/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NISCH	ENST00000345716.9	c.1142A>G	p.Asn381Ser	missense_variant	10/21	1	NM_007184.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251290 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135800

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461818 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727214

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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

Sep 27, 2021

The c.1142A>G (p.N381S) alteration is located in exon 10 (coding exon 10) of the NISCH gene. This alteration results from a A to G substitution at nucleotide position 1142, causing the asparagine (N) at amino acid position 381 to be replaced by a serine (S). 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	0.12
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.38	T;T;.;.
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Benign	0.0082	T
MetaRNN	Benign	0.26	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.17	N;N;.;N
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.8	D;D;D;D
REVEL	Benign	0.14
Sift	Benign	0.062	T;T;T;T
Sift4G	Uncertain	0.0020	D;D;T;T
Polyphen		1.0	D;D;D;.
Vest4		0.16
MutPred		0.34		Loss of catalytic residue at N381 (P = 0.0479);Loss of catalytic residue at N381 (P = 0.0479);Loss of catalytic residue at N381 (P = 0.0479);Loss of catalytic residue at N381 (P = 0.0479);
MVP		0.22
MPC		0.38
ClinPred		0.63	D
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.088
gMVP		0.34

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: rs1344315704; hg19: chr3-52512267; COSMIC: COSV100617631; COSMIC: COSV100617631;