3-52470877-G-A

Position:

chr3-52470877-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4BS2

The NM_007184.4(NISCH):c.379G>A(p.Ala127Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,888 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: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

NISCH
NM_007184.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.84

Variant links:

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]

NISCH links:

NISCH (HGNC:):

NISCH links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.28310028).

BS2

High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NISCH	NM_007184.4 linkuse as main transcript	c.379G>A	p.Ala127Thr	missense_variant	4/21	ENST00000345716.9	NP_009115.3	Q9Y2I1-1
NISCH	NM_001276293.2 linkuse as main transcript	c.379G>A	p.Ala127Thr	missense_variant	4/13		NP_001263222.2	Q9Y2I1
NISCH	NM_001276294.2 linkuse as main transcript	c.379G>A	p.Ala127Thr	missense_variant	4/14		NP_001263223.2	Q9Y2I1-4
NISCH	XM_047447373.1 linkuse as main transcript	c.379G>A	p.Ala127Thr	missense_variant	4/18		XP_047303329.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NISCH	ENST00000345716.9 linkuse as main transcript	c.379G>A	p.Ala127Thr	missense_variant	4/21	1	NM_007184.4	ENSP00000339958.4		Q9Y2I1-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251492

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

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:

0.00000342

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 07, 2023

The c.379G>A (p.A127T) alteration is located in exon 4 (coding exon 4) of the NISCH gene. This alteration results from a G to A substitution at nucleotide position 379, causing the alanine (A) at amino acid position 127 to be replaced by a threonine (T). 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

0.15

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.38

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.14

T;T;.;.

Eigen

Pathogenic

0.69

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

.;D;D;D

M_CAP

Benign

0.0077

MetaRNN

Benign

0.28

T;T;T;T

MetaSVM

Benign

-1.2

MutationAssessor

Benign

1.9

L;L;.;L

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-2.0

N;N;N;N

REVEL

Benign

0.22

Sift

Uncertain

0.014

D;D;T;T

Sift4G

Uncertain

0.0030

D;D;T;T

Polyphen

1.0

D;D;D;.

Vest4

0.34

MutPred

0.38

Loss of glycosylation at T126 (P = 0.1123);Loss of glycosylation at T126 (P = 0.1123);Loss of glycosylation at T126 (P = 0.1123);Loss of glycosylation at T126 (P = 0.1123);

MVP

0.21

MPC

0.54

ClinPred

0.55

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.19

gMVP

0.43

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over