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GeneBe

1-158683388-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_003126.4(SPTA1):c.373G>A(p.Ala125Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00148 in 1,613,308 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00098 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0015 ( 5 hom. )

Consequence

SPTA1
NM_003126.4 missense

Scores

1
10
7

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:2

Conservation

PhyloP100: 3.18
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.2289679).
BP6
Variant 1-158683388-C-T is Benign according to our data. Variant chr1-158683388-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 547874.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Benign=1, Likely_benign=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SPTA1NM_003126.4 linkuse as main transcriptc.373G>A p.Ala125Thr missense_variant 3/52 ENST00000643759.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SPTA1ENST00000643759.2 linkuse as main transcriptc.373G>A p.Ala125Thr missense_variant 3/52 NM_003126.4 P1P02549-1

Frequencies

GnomAD3 genomes
AF:
0.000980
AC:
149
AN:
152088
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000531
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00144
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000942
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00149
Gnomad OTH
AF:
0.00143
GnomAD3 exomes
AF:
0.000742
AC:
185
AN:
249190
Hom.:
1
AF XY:
0.000755
AC XY:
102
AN XY:
135184
show subpopulations
Gnomad AFR exome
AF:
0.0000646
Gnomad AMR exome
AF:
0.000232
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000464
Gnomad NFE exome
AF:
0.00154
Gnomad OTH exome
AF:
0.000166
GnomAD4 exome
AF:
0.00153
AC:
2234
AN:
1461102
Hom.:
5
Cov.:
31
AF XY:
0.00148
AC XY:
1075
AN XY:
726840
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.000358
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.000169
Gnomad4 NFE exome
AF:
0.00193
Gnomad4 OTH exome
AF:
0.00109
GnomAD4 genome
AF:
0.000979
AC:
149
AN:
152206
Hom.:
0
Cov.:
32
AF XY:
0.000873
AC XY:
65
AN XY:
74426
show subpopulations
Gnomad4 AFR
AF:
0.000530
Gnomad4 AMR
AF:
0.00144
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000942
Gnomad4 NFE
AF:
0.00149
Gnomad4 OTH
AF:
0.00142
Alfa
AF:
0.00117
Hom.:
0
Bravo
AF:
0.00106
TwinsUK
AF:
0.00162
AC:
6
ALSPAC
AF:
0.00259
AC:
10
ESP6500AA
AF:
0.000271
AC:
1
ESP6500EA
AF:
0.00171
AC:
14
ExAC
AF:
0.000745
AC:
90
EpiCase
AF:
0.00125
EpiControl
AF:
0.00172

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:3Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeMay 25, 2023- -
Uncertain significance, criteria provided, single submitterclinical testingRevvity Omics, RevvityAug 01, 2023- -
Uncertain significance, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicJun 24, 2022- -
Uncertain significance, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesAug 21, 2020- -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsAug 09, 2021The c.373G>A (p.A125T) alteration is located in exon 3 (coding exon 3) of the SPTA1 gene. This alteration results from a G to A substitution at nucleotide position 373, causing the alanine (A) at amino acid position 125 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
SPTA1-related disorder Benign:1
Likely benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesJul 19, 2022This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.10
BayesDel_addAF
Benign
-0.38
T
BayesDel_noAF
Benign
-0.33
Cadd
Benign
22
Dann
Uncertain
1.0
DEOGEN2
Uncertain
0.48
T;T
Eigen
Uncertain
0.65
Eigen_PC
Uncertain
0.58
FATHMM_MKL
Uncertain
0.95
D
M_CAP
Uncertain
0.26
D
MetaRNN
Benign
0.23
T;T
MetaSVM
Benign
-0.78
T
MutationAssessor
Pathogenic
3.5
H;H
MutationTaster
Benign
1.0
D;D
PrimateAI
Benign
0.46
T
PROVEAN
Uncertain
-3.2
D;.
REVEL
Uncertain
0.40
Sift
Uncertain
0.0040
D;.
Sift4G
Uncertain
0.0080
D;.
Polyphen
0.98
D;D
Vest4
0.42
MVP
0.71
MPC
0.22
ClinPred
0.16
T
GERP RS
6.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.58
gMVP
0.11

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

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

Other links and lift over

dbSNP: rs201771255; hg19: chr1-158653178; API