3-52455654-C-G

Position:

• chr3-52455654-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.13C>G​(p.Arg5Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000335 in 1,344,710 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000037 (0 hom.)
• Consequence: NISCH NM_007184.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08831233).
• BS2: High AC in GnomAdExome4 at 44 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NISCH	NM_007184.4	c.13C>G	p.Arg5Gly	missense_variant	1/21	ENST00000345716.9	NP_009115.3
NISCH	NM_001276293.2	c.13C>G	p.Arg5Gly	missense_variant	1/13		NP_001263222.2
NISCH	NM_001276294.2	c.13C>G	p.Arg5Gly	missense_variant	1/14		NP_001263223.2
NISCH	XM_047447373.1	c.13C>G	p.Arg5Gly	missense_variant	1/18		XP_047303329.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NISCH	ENST00000345716.9	c.13C>G	p.Arg5Gly	missense_variant	1/21	1	NM_007184.4	ENSP00000339958.4
NISCH	ENST00000479054.5	c.13C>G	p.Arg5Gly	missense_variant	2/22	1		ENSP00000418232.1
NISCH	ENST00000488380.5	c.13C>G	p.Arg5Gly	missense_variant	1/13	1		ENSP00000417812.1
NISCH	ENST00000420808.2	c.13C>G	p.Arg5Gly	missense_variant	1/14	5		ENSP00000392484.2

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152046 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000369 AC: 44 AN: 1192664 Hom.: 0 Cov.: 31 AF XY: 0.0000260 AC XY: 15 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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000422

Gnomad4 OTH exome AF: 0.0000634

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152046 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74276

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

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

May 11, 2022

The c.13C>G (p.R5G) alteration is located in exon 1 (coding exon 1) of the NISCH gene. This alteration results from a C to G substitution at nucleotide position 13, causing the arginine (R) at amino acid position 5 to be replaced by a glycine (G). 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	0.064
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	16
DANN	Benign	0.95
DEOGEN2	Benign	0.045	T;T;.;.
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.63	.;T;T;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.088	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.0	N;N;.;N
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.82	N;N;N;N
REVEL	Benign	0.099
Sift	Benign	0.097	T;T;T;T
Sift4G	Benign	0.17	T;T;T;T
Polyphen		0.0	B;B;B;.
Vest4		0.15
MutPred		0.25		Gain of catalytic residue at A4 (P = 0.0259);Gain of catalytic residue at A4 (P = 0.0259);Gain of catalytic residue at A4 (P = 0.0259);Gain of catalytic residue at A4 (P = 0.0259);
MVP		0.068
MPC		0.54
ClinPred		0.070	T
GERP RS		0.76
Varity_R		0.16
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;