NM_007184.4:c.20T>C

Variant names:

• chr3-52455661-T-C
• rs752094665
• NM_007184.4:c.20T>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_007184.4(NISCH):​c.20T>C​(p.Phe7Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000164 in 1,353,478 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: NISCH NM_007184.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.38
• Publications: 2 publications found

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

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.24672943).
• BS2: High AC in GnomAd4 at 17 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007184.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NISCH	NM_007184.4	MANE Select	c.20T>C	p.Phe7Ser	missense	Exon 1 of 21	NP_009115.3	Q9Y2I1-1
	NISCH	NM_001276293.2		c.20T>C	p.Phe7Ser	missense	Exon 1 of 13	NP_001263222.2	C9J715
	NISCH	NM_001276294.2		c.20T>C	p.Phe7Ser	missense	Exon 1 of 14	NP_001263223.2	Q9Y2I1-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NISCH	ENST00000345716.9	TSL:1 MANE Select	c.20T>C	p.Phe7Ser	missense	Exon 1 of 21	ENSP00000339958.4	Q9Y2I1-1
	NISCH	ENST00000479054.5	TSL:1	c.20T>C	p.Phe7Ser	missense	Exon 2 of 22	ENSP00000418232.1	Q9Y2I1-1
	NISCH	ENST00000488380.5	TSL:1	c.20T>C	p.Phe7Ser	missense	Exon 1 of 13	ENSP00000417812.1	C9J715

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 151872 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000116 AC: 15 AN: 128788 AF XY: 0.000133

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000188

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000200

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000171 AC: 205 AN: 1201606 Hom.: 0 Cov.: 31 AF XY: 0.000195 AC XY: 114 AN XY: 583346

African (AFR) AF: 0.000119 AC: 3 AN: 25130

American (AMR) AF: 0.000108 AC: 2 AN: 18466

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18288

East Asian (EAS) AF: 0.00 AC: 0 AN: 30548

South Asian (SAS) AF: 0.00 AC: 0 AN: 40156

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40482

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4788

European-Non Finnish (NFE) AF: 0.000203 AC: 198 AN: 976154

Other (OTH) AF: 0.0000420 AC: 2 AN: 47594

GnomAD4 genome AF: 0.000112 AC: 17 AN: 151872 Hom.: 0 Cov.: 31 AF XY: 0.000121 AC XY: 9 AN XY: 74178

African (AFR) AF: 0.0000484 AC: 2 AN: 41324

American (AMR) AF: 0.000262 AC: 4 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10568

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 67942

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.000174 Hom.: 0

Bravo AF: 0.000249

ExAC AF: 0.0000780 AC: 9

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.055	T
Eigen	Benign	0.13
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.073	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		2.4
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.16
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.15	T
Polyphen		1.0	D
Vest4		0.59
MVP		0.36
MPC		1.4
ClinPred		0.51	D
GERP RS		4.9
PromoterAI		0.036	Neutral
Varity_R		0.55
gMVP		0.16
Mutation Taster		=78/22	polymorphism

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

Other links and lift over

dbSNP: rs752094665; hg19: chr3-52489677;