1-158678434-A-G

Position:

chr1-158678434-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP3_StrongPP5_Very_Strong

The NM_003126.4(SPTA1):c.779T>C(p.Leu260Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,613,700 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

SPTA1
NM_003126.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 8.48

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.991

PP5

Variant 1-158678434-A-G is Pathogenic according to our data. Variant chr1-158678434-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12844.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-158678434-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPTA1	NM_003126.4 linkuse as main transcript	c.779T>C	p.Leu260Pro	missense_variant	6/52	ENST00000643759.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPTA1	ENST00000643759.2 linkuse as main transcript	c.779T>C	p.Leu260Pro	missense_variant	6/52		NM_003126.4	P1	P02549-1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

249130

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135138

show subpopulations

Gnomad AFR exome

AF:

0.000194

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461496

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727058

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

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:

0.00

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.000193

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000453

ExAC

AF:

0.0000248

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 30, 2022	Observed in individuals with hereditary elliptocytosis, however these individuals were not screened for variants in other genes associated with hereditary elliptocytosis (Glele-Kakai et al., 1996); Published functional studies demonstrate that L260P increased the stability of the closed dimer state, reduced tetramer assembly, and resulted in membrane destabilization (Randles et al., 2013; Harper et al., 2013); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 3597773, 23974198, 2794061, 8857939, 31130284, 23241237, 32641076) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 08, 2022	Experimental studies have shown that this missense change affects SPTA1 function (PMID: 23974198). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SPTA1 protein function. ClinVar contains an entry for this variant (Variation ID: 12844). This missense change has been observed in individual(s) with autosomal dominant hereditary elliptocytosis and autosomal recessive hereditary pyropoikilocytosis (PMID: 2794061, 8857939, 18815189, 31130284, 32641076). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs121918634, gnomAD 0.02%). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 260 of the SPTA1 protein (p.Leu260Pro). -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 08, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 24, 2023	- -

Elliptocytosis 2

Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 1989	- -
Pathogenic, criteria provided, single submitter	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Mar 29, 2021	- -
Likely pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 25, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.37

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.72

D;D

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.95

M_CAP

Uncertain

0.24

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Uncertain

0.64

MutationAssessor

Pathogenic

3.6

H;H

MutationTaster

Benign

1.0

A;A

PrimateAI

Uncertain

0.53

PROVEAN

Pathogenic

-6.3

D;.

REVEL

Pathogenic

0.84

Sift

Pathogenic

0.0

D;.

Sift4G

Uncertain

0.013

D;.

Polyphen

1.0

D;D

Vest4

0.93

MutPred

0.91

Loss of stability (P = 0.024);Loss of stability (P = 0.024);

MVP

0.96

MPC

0.26

ClinPred

0.98

GERP RS

4.7

Varity_R

0.97

gMVP

0.91

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over