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rs78394850

chr1-158623057-G-Achr1-158623057-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003126.4(SPTA1):c.6046C>T(p.Arg2016Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0241 in 1,613,990 control chromosomes in the GnomAD database, including 1,324 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2016H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.054 ( 487 hom., cov: 33)
Exomes 𝑓: 0.021 ( 837 hom. )

Consequence

SPTA1
NM_003126.4 missense

Scores

3
5
7

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 9.54
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (MetaRNN=0.0038462281).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 1-158623057-G-A is Benign according to our data. Variant chr1-158623057-G-A is described in ClinVar as [Benign]. Clinvar id is 258951.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-158623057-G-A is described in Lovd as [Benign]. Variant chr1-158623057-G-A is described in Lovd as [Likely_benign].
BA1
?
    BA1 - Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.143 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SPTA1NM_003126.4 linkuse as main transcriptc.6046C>T p.Arg2016Cys missense_variant 43/52 ENST00000643759.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SPTA1ENST00000643759.2 linkuse as main transcriptc.6046C>T p.Arg2016Cys missense_variant 43/52 NM_003126.4 P1P02549-1
SPTA1ENST00000461624.1 linkuse as main transcriptn.592C>T non_coding_transcript_exon_variant 5/52

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0534
AC:
8125
AN:
152048
Hom.:
485
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.145
Gnomad AMI
AF:
0.00110
Gnomad AMR
AF:
0.0271
Gnomad ASJ
AF:
0.0496
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.0460
Gnomad FIN
AF:
0.00952
Gnomad MID
AF:
0.0728
Gnomad NFE
AF:
0.0159
Gnomad OTH
AF:
0.0483
GnomAD3 exomes
AF:
0.0295
AC:
7359
AN:
249486
Hom.:
277
AF XY:
0.0294
AC XY:
3980
AN XY:
135344
show subpopulations
Gnomad AFR exome
AF:
0.144
Gnomad AMR exome
AF:
0.0200
Gnomad ASJ exome
AF:
0.0517
Gnomad EAS exome
AF:
0.000278
Gnomad SAS exome
AF:
0.0502
Gnomad FIN exome
AF:
0.00840
Gnomad NFE exome
AF:
0.0178
Gnomad OTH exome
AF:
0.0301
GnomAD4 exome
AF:
0.0211
AC:
30772
AN:
1461824
Hom.:
837
Cov.:
30
AF XY:
0.0218
AC XY:
15833
AN XY:
727204
show subpopulations
Gnomad4 AFR exome
AF:
0.147
Gnomad4 AMR exome
AF:
0.0210
Gnomad4 ASJ exome
AF:
0.0529
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.0539
Gnomad4 FIN exome
AF:
0.00957
Gnomad4 NFE exome
AF:
0.0144
Gnomad4 OTH exome
AF:
0.0300
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0536
AC:
8157
AN:
152166
Hom.:
487
Cov.:
33
AF XY:
0.0530
AC XY:
3942
AN XY:
74406
show subpopulations
Gnomad4 AFR
AF:
0.146
Gnomad4 AMR
AF:
0.0271
Gnomad4 ASJ
AF:
0.0496
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.0459
Gnomad4 FIN
AF:
0.00952
Gnomad4 NFE
AF:
0.0159
Gnomad4 OTH
AF:
0.0478
Alfa
AF:
0.0237
Hom.:
172
Bravo
AF:
0.0587
TwinsUK
AF:
0.0148
AC:
55
ALSPAC
AF:
0.0163
AC:
63
ESP6500AA
AF:
0.140
AC:
541
ESP6500EA
AF:
0.0158
AC:
131
ExAC
?
    Exome Aggregation Consortium database
AF:
0.0321
AC:
3874
Asia WGS
AF:
0.0290
AC:
100
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:3
Benign, criteria provided, single submitterclinical testingGeneDxFeb 04, 2020This variant is associated with the following publications: (PMID: 27884173, 24193021) -
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesNov 16, 2023- -
Benign, criteria provided, single submitterclinical testingInvitaeJan 25, 2024- -
Elliptocytosis 2 Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
not specified Benign:1
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Hereditary spherocytosis type 3 Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Pyropoikilocytosis, hereditary Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.39
T
BayesDel_noAF
Benign
-0.21
Cadd
Uncertain
24
Dann
Uncertain
1.0
DEOGEN2
Uncertain
0.71
D;D
Eigen
Uncertain
0.66
Eigen_PC
Uncertain
0.54
FATHMM_MKL
Pathogenic
0.99
D
MetaRNN
Benign
0.0038
T;T
MetaSVM
Benign
-0.63
T
MutationAssessor
Pathogenic
3.0
M;M
MutationTaster
Benign
1.0
D;D
PrimateAI
Benign
0.31
T
REVEL
Uncertain
0.34
Sift4G
Pathogenic
0.0
D;.
Polyphen
1.0
D;D
Vest4
0.68
MPC
0.24
ClinPred
0.017
T
GERP RS
4.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.59
gMVP
0.43

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.

Other links and lift over

dbSNP: rs78394850; hg19: chr1-158592847; COSMIC: COSV63756152; COSMIC: COSV63756152; API