chr9-128604414-A-G

Position:

• chr9-128604414-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3 PP5

The NM_001130438.3(SPTAN1):​c.3716A>G​(p.His1239Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPTAN1 NM_001130438.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 8.92

Genes affected

SPTAN1 (HGNC:11273): (spectrin alpha, non-erythrocytic 1) Spectrins are a family of filamentous cytoskeletal proteins that function as essential scaffold proteins that stabilize the plasma membrane and organize intracellular organelles. Spectrins are composed of alpha and beta dimers that associate to form tetramers linked in a head-to-head arrangement. This gene encodes an alpha spectrin that is specifically expressed in nonerythrocytic cells. The encoded protein has been implicated in other cellular functions including DNA repair and cell cycle regulation. Mutations in this gene are the cause of early infantile epileptic encephalopathy-5. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Sep 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SPTAN1. . Gene score misZ 5.523 (greater than the threshold 3.09). Trascript score misZ 7.9287 (greater than threshold 3.09). GenCC has associacion of gene with developmental and epileptic encephalopathy, 5, developmental and epileptic encephalopathy, West syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.758
• PP5: Variant 9-128604414-A-G is Pathogenic according to our data. Variant chr9-128604414-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 521064.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPTAN1	NM_001130438.3	c.3716A>G	p.His1239Arg	missense_variant	29/57	ENST00000372739.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPTAN1	ENST00000372739.7	c.3716A>G	p.His1239Arg	missense_variant	29/57	1	NM_001130438.3	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Developmental and epileptic encephalopathy, 5 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Likely pathogenic, criteria provided, single submitter	research	Institute of Human Genetics, University of Leipzig Medical Center	Sep 01, 2017	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 19, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T;.;.;.;.
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	D;D;D;D;D
M_CAP	Benign	0.065	D
MetaRNN	Pathogenic	0.76	D;D;D;D;D
MetaSVM	Benign	-0.70	T
MutationAssessor	Uncertain	2.3	M;.;M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.0	D;.;D;.;.
REVEL	Uncertain	0.61
Sift	Uncertain	0.010	D;.;D;.;.
Sift4G	Benign	0.20	T;D;T;D;T
Polyphen		0.97	D;.;D;D;.
Vest4		0.76
MutPred		0.52		Loss of catalytic residue at R1237 (P = 0.0389);.;Loss of catalytic residue at R1237 (P = 0.0389);.;Loss of catalytic residue at R1237 (P = 0.0389);
MVP		0.82
MPC		1.8
ClinPred		0.99	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.72
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1554756114; hg19: chr9-131366693;