17-11241516-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_207386.4(SHISA6):c.94A>C(p.Asn32His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 990,406 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: SHISA6 NM_207386.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.775

Genes affected

SHISA6 (HGNC:34491): (shisa family member 6) Predicted to enable ionotropic glutamate receptor binding activity. Predicted to be involved in several processes, including excitatory chemical synaptic transmission; regulation of short-term neuronal synaptic plasticity; and regulation of signal transduction. 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 density membrane. [provided by Alliance of Genome Resources, Apr 2022]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a glycosylation_site N-linked (GlcNAc...) asparagine (size 0) in uniprot entity SHSA6_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13770962).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SHISA6	NM_207386.4	c.94A>C	p.Asn32His	missense_variant	1/6	ENST00000441885.8
SHISA6	NM_001173462.2	c.94A>C	p.Asn32His	missense_variant	1/5
SHISA6	NM_001173461.2	c.94A>C	p.Asn32His	missense_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHISA6	ENST00000441885.8	c.94A>C	p.Asn32His	missense_variant	1/6	5	NM_207386.4
SHISA6	ENST00000432116.7	c.94A>C	p.Asn32His	missense_variant	1/5	1
SHISA6	ENST00000409168.7	c.94A>C	p.Asn32His	missense_variant	1/4	1		P1
	ENST00000648331.1	n.98+449T>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000131 AC: 13 AN: 990406 Hom.: 0 Cov.: 31 AF XY: 0.0000105 AC XY: 5 AN XY: 478316

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: 0.0000151

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 12, 2021

The c.94A>C (p.N32H) alteration is located in exon 1 (coding exon 1) of the SHISA6 gene. This alteration results from a A to C substitution at nucleotide position 94, causing the asparagine (N) at amino acid position 32 to be replaced by a histidine (H). 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	0.27
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	22
Dann	Uncertain	0.99
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.51	T;T;T
M_CAP	Pathogenic	0.44	D
MetaRNN	Benign	0.14	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.58	N;N;N
REVEL	Benign	0.020
Sift	Benign	0.47	T;T;T
Sift4G	Uncertain	0.038	D;D;D
Polyphen		0.40	B;.;B
Vest4		0.16
MutPred		0.14		Loss of methylation at R33 (P = 0.0691);Loss of methylation at R33 (P = 0.0691);Loss of methylation at R33 (P = 0.0691);
MVP		0.040
ClinPred		0.27	T
GERP RS		1.0
Varity_R		0.057
gMVP		0.26

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-11144833;