rs121918637

Variant names:

• chr1-158685237-C-A
• rs121918637
• NM_003126.4:c.135G>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_003126.4(SPTA1):​c.135G>T​(p.Arg45Ser) variant causes a missense change involving the alteration of a non-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 Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R45K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPTA1 NM_003126.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: -0.272
• Publications: 3 publications found

Genes affected

SPTA1 (HGNC:11272): (spectrin alpha, erythrocytic 1) This gene encodes a member of a family of molecular scaffold proteins that link the plasma membrane to the actin cytoskeleton and functions in the determination of cell shape, arrangement of transmembrane proteins, and organization of organelles. The encoded protein is primarily composed of 22 spectrin repeats which are involved in dimer formation. It forms a component of the erythrocyte plasma membrane. Mutations in this gene result in a variety of hereditary red blood cell disorders, including elliptocytosis-2, pyropoikilocytosis, and spherocytosis, type 3. [provided by RefSeq, Aug 2017]

SPTA1 Gene-Disease associations (from GenCC):

• hereditary spherocytosis type 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Ambry Genetics
• elliptocytosis 2

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine
• pyropoikilocytosis, hereditary

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• hereditary elliptocytosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary spherocytosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_003126.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-158685238-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2433756.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.97
• PP5: Variant 1-158685237-C-A is Pathogenic according to our data. Variant chr1-158685237-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 12849.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPTA1	NM_003126.4	c.135G>T	p.Arg45Ser	missense_variant	Exon 2 of 52	ENST00000643759.2	NP_003117.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPTA1	ENST00000643759.2	c.135G>T	p.Arg45Ser	missense_variant	Exon 2 of 52		NM_003126.4	ENSP00000495214.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 50

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Elliptocytosis 2 Pathogenic:1

Apr 01, 1990

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Pyropoikilocytosis, hereditary Pathogenic:1

Apr 01, 1990

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D;D
Eigen	Benign	0.056
Eigen_PC	Benign	-0.090
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.80	.;T
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.6	M;M
PhyloP100		-0.27
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-4.0	D;.
REVEL	Uncertain	0.39
Sift	Uncertain	0.0050	D;.
Sift4G	Uncertain	0.0020	D;.
Polyphen		0.99	D;D
Vest4		0.91
MutPred		0.92		Loss of MoRF binding (P = 0.0354);Loss of MoRF binding (P = 0.0354);
MVP		0.86
MPC		0.23
ClinPred		0.99	D
GERP RS		-1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.69
Mutation Taster		=9/91	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121918637; hg19: chr1-158655027;