Genetic Variant NM_007184.4:c.379G>C (chr3-52470877-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_007184.4(NISCH):c.379G>C(p.Ala127Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

NISCH
NM_007184.4 missense

Scores

Clinical Significance

Not reported in ClinVar

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NISCH	NM_007184.4 link	c.379G>C	p.Ala127Pro	missense_variant	Exon 4 of 21	ENST00000345716.9	NP_009115.3	Q9Y2I1-1
NISCH	NM_001276293.2 link	c.379G>C	p.Ala127Pro	missense_variant	Exon 4 of 13		NP_001263222.2	Q9Y2I1
NISCH	NM_001276294.2 link	c.379G>C	p.Ala127Pro	missense_variant	Exon 4 of 14		NP_001263223.2	Q9Y2I1-4
NISCH	XM_047447373.1 link	c.379G>C	p.Ala127Pro	missense_variant	Exon 4 of 18		XP_047303329.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NISCH	ENST00000345716.9 link	c.379G>C	p.Ala127Pro	missense_variant	Exon 4 of 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:

0.00

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:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727246

show subpopulations

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Uncertain

0.040

BayesDel_noAF

Benign

-0.18

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.20

T;T;.;.

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

.;D;D;D

M_CAP

Benign

0.012

MetaRNN

Uncertain

0.44

T;T;T;T

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.3

M;M;.;M

PrimateAI

Uncertain

0.74

PROVEAN

Uncertain

-2.5

N;N;D;D

REVEL

Benign

0.21

Sift

Uncertain

0.0030

D;D;T;T

Sift4G

Uncertain

0.0040

D;D;T;T

Polyphen

1.0

D;D;D;.

Vest4

0.56

MVP

0.23

MPC

1.4

ClinPred

0.94

GERP RS

5.6

Varity_R

0.76

gMVP

0.87

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over