16-13235057-C-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001145204.3(SHISA9):c.923C>G(p.Thr308Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00001 in 1,399,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: SHISA9 NM_001145204.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.81

Genes affected

SHISA9 (HGNC:37231): (shisa family member 9) Predicted to enable PDZ domain binding activity. Predicted to be involved in regulation of AMPA receptor activity and regulation of short-term neuronal synaptic plasticity. Predicted to be located in 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 density membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.037819713).
• BP6: Variant 16-13235057-C-G is Benign according to our data. Variant chr16-13235057-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 2598314.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SHISA9	NM_001145204.3	c.923C>G	p.Thr308Ser	missense_variant	5/5	ENST00000558583.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHISA9	ENST00000558583.3	c.923C>G	p.Thr308Ser	missense_variant	5/5	5	NM_001145204.3	P1
SHISA9	ENST00000566106.1	n.319C>G		non_coding_transcript_exon_variant	3/3	4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000513 AC: 8 AN: 155896 Hom.: 0 AF XY: 0.0000363 AC XY: 3 AN XY: 82542

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000325

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000100 AC: 14 AN: 1399004 Hom.: 0 Cov.: 34 AF XY: 0.0000116 AC XY: 8 AN XY: 689974

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000336

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: 0.00000185

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.0000302

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 21, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	20
Dann	Benign	0.23
DEOGEN2	Benign	0.0026	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.038	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.0	N
MutationTaster	Benign	0.96	N;N
PrimateAI	Benign	0.36	T
Sift4G	Benign	0.94	T
Polyphen		0.0	B
Vest4		0.050
MutPred		0.18		Gain of disorder (P = 0.037);
MVP		0.048
ClinPred		0.072	T
GERP RS		4.4
Varity_R		0.084
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs879741742; hg19: chr16-13328914;