NM_014575.4:c.496G>A

Variant names:

• chr3-159764875-G-A
• rs1361188535
• NM_014575.4:c.496G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014575.4(SCHIP1):​c.496G>A​(p.Val166Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000019 in 1,580,112 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V166L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SCHIP1 NM_014575.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.00800
• Publications: 2 publications found

Genes affected

SCHIP1 (HGNC:15678): (schwannomin interacting protein 1) Enables identical protein binding activity. Predicted to be involved in positive regulation of hippo signaling. Predicted to act upstream of or within several processes, including animal organ development; face morphogenesis; and fibroblast migration. Located in several cellular components, including cell junction; cytosol; and nuclear body. [provided by Alliance of Genome Resources, Apr 2022]

IQCJ-SCHIP1 (HGNC:38842): (IQCJ-SCHIP1 readthrough) This locus represents naturally occurring read-through transcription from the neighboring IQ motif containing J (IQCJ) and schwannomin interacting protein 1 (SCHIP1) genes. Alternative splicing results in multiple transcript variants that are composed of in-frame exons from each individual gene. The resulting fusion products are thought to be components of the multimolecular complexes of axon initial segments and nodes of Ranvier, and they may play a role in calcium-mediated responses. [provided by RefSeq, Oct 2010]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09058723).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014575.4. 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
	SCHIP1	NM_014575.4	MANE Select	c.496G>A	p.Val166Met	missense	Exon 2 of 8	NP_055390.1	P0DPB3-1
	IQCJ-SCHIP1	NM_001197113.2		c.724G>A	p.Val242Met	missense	Exon 5 of 11	NP_001184042.1	B3KU38-1
	IQCJ-SCHIP1	NM_001197114.2		c.643G>A	p.Val215Met	missense	Exon 4 of 10	NP_001184043.1	B3KU38-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCHIP1	ENST00000638749.2	TSL:1 MANE Select	c.496G>A	p.Val166Met	missense	Exon 2 of 8	ENSP00000491030.1	P0DPB3-1
	IQCJ-SCHIP1	ENST00000485419.7	TSL:2	c.724G>A	p.Val242Met	missense	Exon 5 of 11	ENSP00000420182.1	B3KU38-1
	SCHIP1	ENST00000412423.8	TSL:1	c.496G>A	p.Val166Met	missense	Exon 2 of 8	ENSP00000400942.2	P0DPB3-2

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152032 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.0000111 AC: 2 AN: 179712 AF XY: 0.0000202

Gnomad AFR exome AF: 0.000123

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: 0.0000134

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1428080 Hom.: 0 Cov.: 31 AF XY: 0.00000141 AC XY: 1 AN XY: 707680

African (AFR) AF: 0.0000626 AC: 2 AN: 31964

American (AMR) AF: 0.00 AC: 0 AN: 40810

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25426

East Asian (EAS) AF: 0.00 AC: 0 AN: 36740

South Asian (SAS) AF: 0.00 AC: 0 AN: 81580

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48970

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5694

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1097886

Other (OTH) AF: 0.00 AC: 0 AN: 59010

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152032 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74262

African (AFR) AF: 0.00 AC: 0 AN: 41422

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5144

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67950

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0086	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.091	T
MetaSVM	Benign	-1.1	T
PhyloP100		0.0080
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	0.35	N
REVEL	Benign	0.032
Sift	Uncertain	0.020	D
Sift4G	Benign	0.097	T
Polyphen		0.042	B
Vest4		0.16
MutPred		0.25		Loss of catalytic residue at V166 (P = 0.064)
MVP		0.22
MPC		0.32
ClinPred		0.074	T
GERP RS		2.4
PromoterAI		0.19	Neutral
Varity_R		0.040
gMVP		0.13
Mutation Taster		=99/1	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: rs1361188535; hg19: chr3-159482664; COSMIC: COSV61843749; COSMIC: COSV61843749;