19-55433323-C-A

Variant names:

• chr19-55433323-C-A
• rs1015595671
• NM_001145176.2:c.1450G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001145176.2(SHISA7):​c.1450G>T​(p.Gly484Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000764 in 1,308,702 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. G484S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
• Consequence: SHISA7 NM_001145176.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.350
• Publications: 0 publications found

Genes affected

SHISA7 (HGNC:35409): (shisa family member 7) Predicted to enable GABA receptor binding activity and ionotropic glutamate receptor binding activity. Predicted to be involved in several processes, including gamma-aminobutyric acid receptor clustering; regulation of signaling receptor activity; and regulation of synaptic plasticity. Predicted to be located in asymmetric, glutamatergic, excitatory synapse. Predicted to be part of AMPA glutamate receptor complex. Predicted to be active in glutamatergic synapse; postsynaptic density; and synaptic membrane. Predicted to be integral component of postsynaptic specialization membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29136628).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001145176.2. 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
	SHISA7	NM_001145176.2	MANE Select	c.1450G>T	p.Gly484Cys	missense	Exon 4 of 4	NP_001138648.1	A6NL88

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHISA7	ENST00000376325.10	TSL:2 MANE Select	c.1450G>T	p.Gly484Cys	missense	Exon 4 of 4	ENSP00000365503.3	A6NL88
	SHISA7	ENST00000416792.2	TSL:5	c.1516G>T	p.Gly506Cys	missense	Exon 5 of 5	ENSP00000401307.2	H7C1N4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.64e-7 AC: 1 AN: 1308702 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 642488

African (AFR) AF: 0.00 AC: 0 AN: 26174

American (AMR) AF: 0.00 AC: 0 AN: 25588

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20554

East Asian (EAS) AF: 0.00 AC: 0 AN: 30092

South Asian (SAS) AF: 0.0000148 AC: 1 AN: 67722

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32198

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3886

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1048026

Other (OTH) AF: 0.00 AC: 0 AN: 54462

GnomAD4 genome Cov.: 32

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	0.26
BayesDel_addAF	Benign	-0.050	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.020	T
Eigen	Benign	-0.016
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.54	T
M_CAP	Pathogenic	0.88	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.35
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.18
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.019	D
Polyphen		1.0	D
Vest4		0.31
MutPred		0.16		Loss of relative solvent accessibility (P = 0.0071)
MVP		0.31
ClinPred		0.76	D
GERP RS		3.0
Varity_R		0.19
gMVP		0.39
Mutation Taster		=74/26	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: rs1015595671; hg19: chr19-55944690;