22-41909929-C-T

Variant names:

• chr22-41909929-C-T
• NM_001207020.3:c.1030G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001207020.3(SHISA8):​c.1030G>A​(p.Ala344Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000073 in 1,369,002 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 33)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: SHISA8 NM_001207020.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.306

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.095604).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHISA8	NM_001207020.3	c.1030G>A	p.Ala344Thr	missense_variant	Exon 4 of 4	ENST00000621082.2	NP_001193949.1
SHISA8	NM_001353438.2	c.1315G>A	p.Ala439Thr	missense_variant	Exon 4 of 4		NP_001340367.1
SHISA8	NM_001353439.2	c.1207G>A	p.Ala403Thr	missense_variant	Exon 4 of 4		NP_001340368.1
SHISA8	XM_006724256.5	c.1195G>A	p.Ala399Thr	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	c.1030G>A	p.Ala344Thr	missense_variant	Exon 4 of 4	5	NM_001207020.3	ENSP00000481203.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.30e-7 AC: 1 AN: 1369002 Hom.: 0 Cov.: 31 AF XY: 0.00000148 AC XY: 1 AN XY: 674890

Gnomad4 AFR exome AF: 0.00

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: 0.00

Gnomad4 NFE exome AF: 9.32e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 17, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1030G>A (p.A344T) alteration is located in exon 4 (coding exon 4) of the SHISA8 gene. This alteration results from a G to A substitution at nucleotide position 1030, causing the alanine (A) at amino acid position 344 to be replaced by a threonine (T). 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	0.075
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	13
DANN	Benign	0.78
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.47	T
MetaRNN	Benign	0.096	T
PrimateAI	Uncertain	0.76	T
Sift4G	Benign	0.71	T
Vest4		0.048
MVP		0.18
GERP RS		-0.36
Varity_R		0.020
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-42305933;