3-52455693-G-A

Position:

• chr3-52455693-G-A

Variant summary

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

The NM_007184.4(NISCH):​c.52G>A​(p.Glu18Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000586 in 1,365,522 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: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000058 (0 hom.)
• Consequence: NISCH NM_007184.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.79

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=0.09450185).
• BS2: High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NISCH	NM_007184.4	c.52G>A	p.Glu18Lys	missense_variant	1/21	ENST00000345716.9	NP_009115.3
NISCH	NM_001276293.2	c.52G>A	p.Glu18Lys	missense_variant	1/13		NP_001263222.2
NISCH	NM_001276294.2	c.52G>A	p.Glu18Lys	missense_variant	1/14		NP_001263223.2
NISCH	XM_047447373.1	c.52G>A	p.Glu18Lys	missense_variant	1/18		XP_047303329.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NISCH	ENST00000345716.9	c.52G>A	p.Glu18Lys	missense_variant	1/21	1	NM_007184.4	ENSP00000339958.4
NISCH	ENST00000479054.5	c.52G>A	p.Glu18Lys	missense_variant	2/22	1		ENSP00000418232.1
NISCH	ENST00000488380.5	c.52G>A	p.Glu18Lys	missense_variant	1/13	1		ENSP00000417812.1
NISCH	ENST00000420808.2	c.52G>A	p.Glu18Lys	missense_variant	1/14	5		ENSP00000392484.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152196 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: 0.00000577 AC: 7 AN: 1213326 Hom.: 0 Cov.: 31 AF XY: 0.00000678 AC XY: 4 AN XY: 590200

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: 0.00000713

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152196 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74338

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

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

Jan 17, 2024

The c.52G>A (p.E18K) alteration is located in exon 1 (coding exon 1) of the NISCH gene. This alteration results from a G to A substitution at nucleotide position 52, causing the glutamic acid (E) at amino acid position 18 to be replaced by a lysine (K). 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	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.060	T;T;.;.
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.023
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.84	.;T;D;D
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.095	T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.040	N;N;.;N
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.2	N;N;N;N
REVEL	Benign	0.035
Sift	Benign	0.39	T;T;T;T
Sift4G	Benign	0.085	T;T;T;T
Polyphen		0.0080	B;B;B;.
Vest4		0.20
MutPred		0.49		Gain of loop (P = 0.0045);Gain of loop (P = 0.0045);Gain of loop (P = 0.0045);Gain of loop (P = 0.0045);
MVP		0.082
MPC		1.2
ClinPred		0.91	D
GERP RS		4.9
Varity_R		0.40
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: rs1317884426; hg19: chr3-52489709;