GeneBe

NM_003126.4:c.5507A>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.5507A>G​(p.Asn1836Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0236 in 1,614,126 control chromosomes in the GnomAD database, including 1,302 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.053 ( 484 hom., cov: 32)
Exomes 𝑓: 0.020 ( 818 hom. )

Consequence

SPTA1
NM_003126.4 missense

Scores

1
17

Clinical Significance

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

Conservation

PhyloP100: 1.26
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 Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0015079081).
BP6
Variant 1-158634601-T-C is Benign according to our data. Variant chr1-158634601-T-C is described in ClinVar as [Benign]. Clinvar id is 258947.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-158634601-T-C is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.142 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SPTA1NM_003126.4 linkc.5507A>G p.Asn1836Ser missense_variant Exon 39 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.5507A>G p.Asn1836Ser missense_variant Exon 39 of 52 NM_003126.4 ENSP00000495214.1 P02549-1
SPTA1ENST00000461624.1 linkn.53A>G non_coding_transcript_exon_variant Exon 1 of 5 2

Frequencies

GnomAD3 genomes
AF:
0.0530
AC:
8063
AN:
152154
Hom.:
482
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.145
Gnomad AMI
AF:
0.00110
Gnomad AMR
AF:
0.0268
Gnomad ASJ
AF:
0.0496
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.0459
Gnomad FIN
AF:
0.00885
Gnomad MID
AF:
0.0728
Gnomad NFE
AF:
0.0153
Gnomad OTH
AF:
0.0483
GnomAD3 exomes
AF:
0.0291
AC:
7267
AN:
249390
Hom.:
274
AF XY:
0.0291
AC XY:
3938
AN XY:
135298
show subpopulations
Gnomad AFR exome
AF:
0.144
Gnomad AMR exome
AF:
0.0198
Gnomad ASJ exome
AF:
0.0517
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:
0.0205
AC:
29927
AN:
1461854
Hom.:
818
Cov.:
32
AF XY:
0.0213
AC XY:
15462
AN XY:
727222
show subpopulations
Gnomad4 AFR exome
AF:
0.146
Gnomad4 AMR exome
AF:
0.0209
Gnomad4 ASJ exome
AF:
0.0529
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.0539
Gnomad4 FIN exome
AF:
0.00929
Gnomad4 NFE exome
AF:
0.0138
Gnomad4 OTH exome
AF:
0.0293
GnomAD4 genome
AF:
0.0532
AC:
8095
AN:
152272
Hom.:
484
Cov.:
32
AF XY:
0.0525
AC XY:
3910
AN XY:
74454
show subpopulations
Gnomad4 AFR
AF:
0.145
Gnomad4 AMR
AF:
0.0267
Gnomad4 ASJ
AF:
0.0496
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.0457
Gnomad4 FIN
AF:
0.00885
Gnomad4 NFE
AF:
0.0153
Gnomad4 OTH
AF:
0.0478
Alfa
AF:
0.0241
Hom.:
288
Bravo
AF:
0.0583
TwinsUK
AF:
0.0135
AC:
50
ALSPAC
AF:
0.0143
AC:
55
ESP6500AA
AF:
0.139
AC:
544
ESP6500EA
AF:
0.0151
AC:
125
ExAC
AF:
0.0316
AC:
3825
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

- -

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

- -

Jun 09, 2021
GeneDx
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

- -

Elliptocytosis 2 Benign:1
Jan 12, 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. -

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

- -

Hereditary spherocytosis type 3 Benign:1
Jan 12, 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 12, 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
0.053
BayesDel_addAF
Benign
-0.74
T
BayesDel_noAF
Benign
-0.72
CADD
Benign
11
DANN
Benign
0.89
DEOGEN2
Benign
0.29
T;T
Eigen
Benign
-1.0
Eigen_PC
Benign
-0.82
FATHMM_MKL
Benign
0.20
N
LIST_S2
Uncertain
0.90
.;D
MetaRNN
Benign
0.0015
T;T
MetaSVM
Benign
-0.97
T
MutationAssessor
Benign
-0.18
N;N
PrimateAI
Benign
0.25
T
PROVEAN
Benign
-1.7
N;.
REVEL
Benign
0.074
Sift
Benign
0.68
T;.
Sift4G
Benign
0.78
T;.
Polyphen
0.0020
B;B
Vest4
0.037
MPC
0.025
ClinPred
0.010
T
GERP RS
1.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.047
gMVP
0.031

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: rs16830483; hg19: chr1-158604391; COSMIC: COSV63756982; COSMIC: COSV63756982; API