3-52473822-C-G

Variant names:

• chr3-52473822-C-G
• rs748430765
• NM_007184.4:c.758C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_007184.4(NISCH):​c.758C>G​(p.Ser253Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,453,810 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S253L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NISCH NM_007184.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.77
• Publications: 1 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.758C>G	p.Ser253Trp	missense	Exon 7 of 21	NP_009115.3	Q9Y2I1-1
	NISCH	NM_001276293.2		c.758C>G	p.Ser253Trp	missense	Exon 7 of 13	NP_001263222.2	C9J715
	NISCH	NM_001276294.2		c.758C>G	p.Ser253Trp	missense	Exon 7 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.758C>G	p.Ser253Trp	missense	Exon 7 of 21	ENSP00000339958.4	Q9Y2I1-1
	NISCH	ENST00000479054.5	TSL:1	c.758C>G	p.Ser253Trp	missense	Exon 8 of 22	ENSP00000418232.1	Q9Y2I1-1
	NISCH	ENST00000488380.5	TSL:1	c.758C>G	p.Ser253Trp	missense	Exon 7 of 13	ENSP00000417812.1	C9J715

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000402 AC: 1 AN: 248472 AF XY: 0.00000745

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000890

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1453810 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 722104

African (AFR) AF: 0.0000300 AC: 1 AN: 33340

American (AMR) AF: 0.00 AC: 0 AN: 44532

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26076

East Asian (EAS) AF: 0.00 AC: 0 AN: 39398

South Asian (SAS) AF: 0.00 AC: 0 AN: 85636

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53236

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5390

European-Non Finnish (NFE) AF: 9.04e-7 AC: 1 AN: 1106164

Other (OTH) AF: 0.00 AC: 0 AN: 60038

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.44	T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.040	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		3.8
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Benign	0.19
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.68
MutPred		0.46		Loss of disorder (P = 0.0034)
MVP		0.37
MPC		1.5
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.46
gMVP		0.72
Mutation Taster		=67/33	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: rs748430765; hg19: chr3-52507838;