Genetic Variant SHISA8:p.Leu302Phe (chr22-41910053-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001207020.3(SHISA8):c.906G>C(p.Leu302Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000496 in 1,255,012 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 8/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00061 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00048 ( 1 hom. )

Consequence

SHISA8
NM_001207020.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.22

Variant links:

Genes affected

SHISA8 (HGNC:18351): (shisa family member 8) Predicted to be involved in regulation of AMPA receptor activity and regulation of short-term neuronal synaptic plasticity. Predicted to be integral component of membrane. Predicted to be part of AMPA glutamate receptor complex. Predicted to be active in dendritic spine membrane; postsynaptic density; and postsynaptic membrane. [provided by Alliance of Genome Resources, Apr 2022]

SHISA8 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.054276496).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
SHISA8	NM_001207020.3 link	c.906G>C	p.Leu302Phe	missense_variant	Exon 4 of 4	ENST00000621082.2	NP_001193949.1
SHISA8	NM_001353438.2 link	c.1191G>C	p.Leu397Phe	missense_variant	Exon 4 of 4		NP_001340367.1
SHISA8	NM_001353439.2 link	c.1083G>C	p.Leu361Phe	missense_variant	Exon 4 of 4		NP_001340368.1
SHISA8	XM_006724256.5 link	c.1071G>C	p.Leu357Phe	missense_variant	Exon 4 of 4		XP_006724319.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHISA8	ENST00000621082.2 link	c.906G>C	p.Leu302Phe	missense_variant	Exon 4 of 4	5	NM_001207020.3	ENSP00000481203.1		B8ZZ34-1

Frequencies

GnomAD3 genomes

AF:

0.000606

AC:

AN:

151814

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00390

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000692

Gnomad OTH

AF:

0.000480

GnomAD4 exome

AF:

0.000480

AC:

530

AN:

1103090

Hom.:

Cov.:

AF XY:

0.000477

AC XY:

250

AN XY:

523660

show subpopulations

Gnomad4 AFR exome

AF:

0.0000440

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00375

Gnomad4 NFE exome

AF:

0.000455

Gnomad4 OTH exome

AF:

0.000402

GnomAD4 genome

AF:

0.000606

AC:

AN:

151922

Hom.:

Cov.:

AF XY:

0.000660

AC XY:

AN XY:

74276

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00390

Gnomad4 NFE

AF:

0.000692

Gnomad4 OTH

AF:

0.000475

Alfa

AF:

0.00127

Hom.:

Bravo

AF:

0.000298

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 29, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.906G>C (p.L302F) alteration is located in exon 4 (coding exon 4) of the SHISA8 gene. This alteration results from a G to C substitution at nucleotide position 906, causing the leucine (L) at amino acid position 302 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Benign

0.42

FATHMM_MKL

Benign

0.42

LIST_S2

Benign

0.50

MetaRNN

Benign

0.054

PrimateAI

Pathogenic

0.86

Sift4G

Uncertain

0.041

Vest4

0.098

MVP

0.24

GERP RS

3.0

Varity_R

0.055

gMVP

0.17

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over