rs863931

Variant summary

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

The NM_003126.4(SPTA1):c.4702T>C(p.Cys1568Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.571 in 1,613,184 control chromosomes in the GnomAD database, including 264,753 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C1568H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.60 ( 27944 hom., cov: 31)

Exomes 𝑓: 0.57 ( 236809 hom. )

Consequence

SPTA1
NM_003126.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.976

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=4.015965E-6).

BP6

Variant 1-158642446-A-G is Benign according to our data. Variant chr1-158642446-A-G is described in ClinVar as [Benign]. Clinvar id is 258942.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-158642446-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.659 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPTA1	NM_003126.4 linkuse as main transcript	c.4702T>C	p.Cys1568Arg	missense_variant	33/52	ENST00000643759.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPTA1	ENST00000643759.2 linkuse as main transcript	c.4702T>C	p.Cys1568Arg	missense_variant	33/52		NM_003126.4	P1	P02549-1
SPTA1	ENST00000465741.1 linkuse as main transcript	n.87T>C		non_coding_transcript_exon_variant	1/3	3

Frequencies

GnomAD3 genomes

AF:

0.603

AC:

91602

AN:

151878

Hom.:

27885

Cov.:

show subpopulations

Gnomad AFR

AF:

0.665

Gnomad AMI

AF:

0.554

Gnomad AMR

AF:

0.582

Gnomad ASJ

AF:

0.631

Gnomad EAS

AF:

0.632

Gnomad SAS

AF:

0.478

Gnomad FIN

AF:

0.647

Gnomad MID

AF:

0.687

Gnomad NFE

AF:

0.569

Gnomad OTH

AF:

0.606

GnomAD3 exomes

AF:

0.578

AC:

143919

AN:

248976

Hom.:

42082

AF XY:

0.573

AC XY:

77445

AN XY:

135066

show subpopulations

Gnomad AFR exome

AF:

0.666

Gnomad AMR exome

AF:

0.565

Gnomad ASJ exome

AF:

0.640

Gnomad EAS exome

AF:

0.616

Gnomad SAS exome

AF:

0.480

Gnomad FIN exome

AF:

0.643

Gnomad NFE exome

AF:

0.572

Gnomad OTH exome

AF:

0.581

GnomAD4 exome

AF:

0.568

AC:

829521

AN:

1461188

Hom.:

236809

Cov.:

AF XY:

0.565

AC XY:

410767

AN XY:

726912

show subpopulations

Gnomad4 AFR exome

AF:

0.676

Gnomad4 AMR exome

AF:

0.568

Gnomad4 ASJ exome

AF:

0.639

Gnomad4 EAS exome

AF:

0.607

Gnomad4 SAS exome

AF:

0.483

Gnomad4 FIN exome

AF:

0.640

Gnomad4 NFE exome

AF:

0.563

Gnomad4 OTH exome

AF:

0.586

GnomAD4 genome

AF:

0.603

AC:

91719

AN:

151996

Hom.:

27944

Cov.:

AF XY:

0.607

AC XY:

45118

AN XY:

74300

show subpopulations

Gnomad4 AFR

AF:

0.666

Gnomad4 AMR

AF:

0.582

Gnomad4 ASJ

AF:

0.631

Gnomad4 EAS

AF:

0.632

Gnomad4 SAS

AF:

0.478

Gnomad4 FIN

AF:

0.647

Gnomad4 NFE

AF:

0.569

Gnomad4 OTH

AF:

0.609

Alfa

AF:

0.579

Hom.:

41807

Bravo

AF:

0.605

TwinsUK

AF:

0.557

AC:

2065

ALSPAC

AF:

0.557

AC:

2148

ESP6500AA

AF:

0.678

AC:

2688

ESP6500EA

AF:

0.562

AC:

4689

ExAC

AF:

0.579

AC:

69915

Asia WGS

AF:

0.599

AC:

2080

AN:

3476

EpiCase

AF:

0.575

EpiControl

AF:

0.574

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

Elliptocytosis 2

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

Hereditary spherocytosis type 3

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

Pyropoikilocytosis, hereditary

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.036

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.69

Cadd

Benign

7.8

Dann

Benign

0.22

DEOGEN2

Benign

0.17

T;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.11

MetaRNN

Benign

0.0000040

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-2.8

N;N

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.27

PROVEAN

Benign

4.1

N;.

REVEL

Benign

0.049

Sift

Benign

1.0

T;.

Sift4G

Benign

1.0

T;.

Polyphen

0.0

B;B

Vest4

0.071

MPC

0.038

ClinPred

0.0043

GERP RS

1.0

Varity_R

0.13

gMVP

0.090

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