GeneBe

1-158623111-C-G

Variant names:

Variant summary

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

The NM_003126.4(SPTA1):​c.5992G>C​(p.Ala1998Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0235 in 1,613,978 control chromosomes in the GnomAD database, including 1,310 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.053 ( 491 hom., cov: 32)
Exomes 𝑓: 0.020 ( 819 hom. )

Consequence

SPTA1
NM_003126.4 missense

Scores

6
10

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 3.79
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
Computational evidence support a benign effect (MetaRNN=0.0021986663).
BP6
Variant 1-158623111-C-G is Benign according to our data. Variant chr1-158623111-C-G is described in ClinVar as [Benign]. Clinvar id is 258950.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-158623111-C-G is described in Lovd as [Benign].
BA1
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 rank MANE Protein UniProt
SPTA1NM_003126.4 linkc.5992G>C p.Ala1998Pro missense_variant Exon 43 of 52 ENST00000643759.2 NP_003117.2 P02549-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SPTA1ENST00000643759.2 linkc.5992G>C p.Ala1998Pro missense_variant Exon 43 of 52 NM_003126.4 ENSP00000495214.1 P02549-1
SPTA1ENST00000461624.1 linkn.538G>C non_coding_transcript_exon_variant Exon 5 of 5 2

Frequencies

GnomAD3 genomes
AF:
0.0531
AC:
8078
AN:
152102
Hom.:
489
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.145
Gnomad AMI
AF:
0.00110
Gnomad AMR
AF:
0.0268
Gnomad ASJ
AF:
0.0495
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.0456
Gnomad FIN
AF:
0.00885
Gnomad MID
AF:
0.0728
Gnomad NFE
AF:
0.0153
Gnomad OTH
AF:
0.0479
GnomAD3 exomes
AF:
0.0292
AC:
7273
AN:
249460
Hom.:
274
AF XY:
0.0291
AC XY:
3936
AN XY:
135334
show subpopulations
Gnomad AFR exome
AF:
0.145
Gnomad AMR exome
AF:
0.0198
Gnomad ASJ exome
AF:
0.0518
Gnomad EAS exome
AF:
0.000278
Gnomad SAS exome
AF:
0.0501
Gnomad FIN exome
AF:
0.00812
Gnomad NFE exome
AF:
0.0171
Gnomad OTH exome
AF:
0.0297
GnomAD4 exome
AF:
0.0204
AC:
29881
AN:
1461758
Hom.:
819
Cov.:
30
AF XY:
0.0212
AC XY:
15442
AN XY:
727186
show subpopulations
Gnomad4 AFR exome
AF:
0.147
Gnomad4 AMR exome
AF:
0.0209
Gnomad4 ASJ exome
AF:
0.0528
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.0539
Gnomad4 FIN exome
AF:
0.00929
Gnomad4 NFE exome
AF:
0.0137
Gnomad4 OTH exome
AF:
0.0293
GnomAD4 genome
AF:
0.0533
AC:
8110
AN:
152220
Hom.:
491
Cov.:
32
AF XY:
0.0526
AC XY:
3915
AN XY:
74418
show subpopulations
Gnomad4 AFR
AF:
0.146
Gnomad4 AMR
AF:
0.0267
Gnomad4 ASJ
AF:
0.0495
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.0455
Gnomad4 FIN
AF:
0.00885
Gnomad4 NFE
AF:
0.0153
Gnomad4 OTH
AF:
0.0474
Alfa
AF:
0.0185
Hom.:
59
Bravo
AF:
0.0585
TwinsUK
AF:
0.0135
AC:
50
ALSPAC
AF:
0.0145
AC:
56
ESP6500AA
AF:
0.141
AC:
550
ESP6500EA
AF:
0.0152
AC:
126
ExAC
AF:
0.0317
AC:
3833
Asia WGS
AF:
0.0290
AC:
100
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:4
Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 24, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Breakthrough Genomics, Breakthrough Genomics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Feb 04, 2020
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 27884173, 24193021) -

not specified Benign:1
-
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Elliptocytosis 2 Benign:1
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This 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. -

Hereditary spherocytosis type 3 Benign:1
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This 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
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This 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
0.33
BayesDel_addAF
Benign
-0.48
T
BayesDel_noAF
Benign
-0.33
CADD
Benign
19
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.63
D;D
Eigen
Uncertain
0.26
Eigen_PC
Benign
0.12
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Benign
0.48
.;T
MetaRNN
Benign
0.0022
T;T
MetaSVM
Benign
-0.72
T
MutationAssessor
Uncertain
2.8
M;M
PrimateAI
Benign
0.38
T
REVEL
Benign
0.25
Sift4G
Uncertain
0.0040
D;.
Polyphen
0.96
D;D
Vest4
0.47
MPC
0.20
ClinPred
0.017
T
GERP RS
3.9
Varity_R
0.77
gMVP
0.40

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: rs77877855; hg19: chr1-158592901; API