rs942861981

Variant names:

• chr9-128568896-G-A
• rs942861981
• NM_001130438.3:c.362G>A

Your query was ambiguous. Multiple possible variants found:

• chr9-128568896-G-A
• chr9-128568896-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001130438.3(SPTAN1):​c.362G>A​(p.Arg121Gln) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,684 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R121L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SPTAN1 NM_001130438.3 missense, splice_region
• Scores: Splicing: ADA: 0.9755
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.52
• Publications: 0 publications found

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]

SPTAN1 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 5

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, G2P, Ambry Genetics
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• neuronopathy, distal hereditary motor, autosomal dominant 11

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
• spastic paraplegia 91, autosomal dominant, with or without cerebellar ataxia

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
• infantile spasms

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary spastic paraplegia

  Inheritance: AR Classification: LIMITED Submitted by: PanelApp Australia

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001130438.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTAN1	NM_001130438.3	MANE Select	c.362G>A	p.Arg121Gln	missense splice_region	Exon 3 of 57	NP_001123910.1	Q13813-2
	SPTAN1	NM_001375318.1		c.398G>A	p.Arg133Gln	missense splice_region	Exon 4 of 59	NP_001362247.1
	SPTAN1	NM_001375310.1		c.362G>A	p.Arg121Gln	missense splice_region	Exon 3 of 58	NP_001362239.1	A0A994J6W3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTAN1	ENST00000372739.7	TSL:1 MANE Select	c.362G>A	p.Arg121Gln	missense splice_region	Exon 3 of 57	ENSP00000361824.4	Q13813-2
	SPTAN1	ENST00000372731.8	TSL:1	c.362G>A	p.Arg121Gln	missense splice_region	Exon 3 of 56	ENSP00000361816.4	Q13813-1
	SPTAN1	ENST00000358161.9	TSL:1	c.362G>A	p.Arg121Gln	missense splice_region	Exon 3 of 55	ENSP00000350882.6	Q13813-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461684 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727130

African (AFR) AF: 0.0000299 AC: 1 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111892

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Developmental and epileptic encephalopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Uncertain	0.072	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.027	D
MetaRNN	Uncertain	0.47	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.29	N
PhyloP100		9.5
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.23
Sift	Benign	0.42	T
Sift4G	Benign	0.30	T
Polyphen		0.64	P
Vest4		0.62
MutPred		0.48		Loss of MoRF binding (P = 0.0408)
MVP		0.73
MPC		0.95
ClinPred		0.88	D
GERP RS		5.9
PromoterAI		-0.11	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.40
gMVP		0.31
Mutation Taster		=33/67	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Benign	0.65
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

Other links and lift over

dbSNP: rs942861981; hg19: chr9-131331175;