rs952094

Variant summary

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

The NM_003126.4(SPTA1):c.6794T>C(p.Ile2265Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.539 in 1,567,036 control chromosomes in the GnomAD database, including 231,666 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.52 ( 20835 hom., cov: 30)

Exomes 𝑓: 0.54 ( 210831 hom. )

Consequence

SPTA1
NM_003126.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.96

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=5.061558E-6).

BP6

Variant 1-158614301-A-G is Benign according to our data. Variant chr1-158614301-A-G is described in ClinVar as [Benign]. Clinvar id is 258957.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-158614301-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.603 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SPTA1	NM_003126.4 linkuse as main transcript	c.6794T>C	p.Ile2265Thr	missense_variant	49/52	ENST00000643759.2
SPTA1	XM_011509916.3 linkuse as main transcript	c.6794T>C	p.Ile2265Thr	missense_variant	50/53
SPTA1	XM_011509917.4 linkuse as main transcript	c.6776T>C	p.Ile2259Thr	missense_variant	48/51
SPTA1	XM_047428883.1 linkuse as main transcript	c.6473T>C	p.Ile2158Thr	missense_variant	49/52

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPTA1	ENST00000643759.2 linkuse as main transcript	c.6794T>C	p.Ile2265Thr	missense_variant	49/52		NM_003126.4	P1	P02549-1
SPTA1	ENST00000481212.5 linkuse as main transcript	n.235T>C		non_coding_transcript_exon_variant	1/3	3
SPTA1	ENST00000498708.1 linkuse as main transcript	n.226T>C		non_coding_transcript_exon_variant	3/5	3

Frequencies

GnomAD3 genomes

AF:

0.520

AC:

78608

AN:

151026

Hom.:

20809

Cov.:

show subpopulations

Gnomad AFR

AF:

0.423

Gnomad AMI

AF:

0.553

Gnomad AMR

AF:

0.544

Gnomad ASJ

AF:

0.570

Gnomad EAS

AF:

0.621

Gnomad SAS

AF:

0.431

Gnomad FIN

AF:

0.633

Gnomad MID

AF:

0.611

Gnomad NFE

AF:

0.552

Gnomad OTH

AF:

0.539

GnomAD3 exomes

AF:

0.537

AC:

129167

AN:

240394

Hom.:

35748

AF XY:

0.534

AC XY:

69765

AN XY:

130546

show subpopulations

Gnomad AFR exome

AF:

0.421

Gnomad AMR exome

AF:

0.538

Gnomad ASJ exome

AF:

0.576

Gnomad EAS exome

AF:

0.606

Gnomad SAS exome

AF:

0.418

Gnomad FIN exome

AF:

0.635

Gnomad NFE exome

AF:

0.551

Gnomad OTH exome

AF:

0.544

GnomAD4 exome

AF:

0.541

AC:

765443

AN:

1415894

Hom.:

210831

Cov.:

AF XY:

0.538

AC XY:

379705

AN XY:

705974

show subpopulations

Gnomad4 AFR exome

AF:

0.421

Gnomad4 AMR exome

AF:

0.541

Gnomad4 ASJ exome

AF:

0.576

Gnomad4 EAS exome

AF:

0.598

Gnomad4 SAS exome

AF:

0.424

Gnomad4 FIN exome

AF:

0.630

Gnomad4 NFE exome

AF:

0.546

Gnomad4 OTH exome

AF:

0.546

GnomAD4 genome

AF:

0.521

AC:

78681

AN:

151142

Hom.:

20835

Cov.:

AF XY:

0.526

AC XY:

38759

AN XY:

73716

show subpopulations

Gnomad4 AFR

AF:

0.423

Gnomad4 AMR

AF:

0.544

Gnomad4 ASJ

AF:

0.570

Gnomad4 EAS

AF:

0.621

Gnomad4 SAS

AF:

0.432

Gnomad4 FIN

AF:

0.633

Gnomad4 NFE

AF:

0.552

Gnomad4 OTH

AF:

0.544

Alfa

AF:

0.548

Hom.:

56062

Bravo

AF:

0.515

TwinsUK

AF:

0.543

AC:

2013

ALSPAC

AF:

0.540

AC:

2083

ESP6500AA

AF:

0.430

AC:

1554

ESP6500EA

AF:

0.541

AC:

4396

ExAC

AF:

0.538

AC:

64923

Asia WGS

AF:

0.553

AC:

1914

AN:

3462

EpiCase

AF:

0.554

EpiControl

AF:

0.550

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

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 12, 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 12, 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	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.69

Cadd

Benign

Dann

Benign

0.12

DEOGEN2

Benign

0.18

T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.94

FATHMM_MKL

Benign

0.052

MetaRNN

Benign

0.0000051

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-0.95

N;N

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.33

REVEL

Benign

0.047

Sift4G

Benign

1.0

T;.

Polyphen

0.0

B;B

Vest4

0.057

MPC

0.031

ClinPred

0.0016

GERP RS

1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.024

gMVP

0.16

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