rs35948326

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_003126.4(SPTA1):c.2909C>A(p.Ala970Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0413 in 1,613,594 control chromosomes in the GnomAD database, including 1,587 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.033 ( 111 hom., cov: 32)

Exomes 𝑓: 0.042 ( 1476 hom. )

Consequence

SPTA1
NM_003126.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:7

Conservation

PhyloP100: 5.33

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=0.0029602945).

BP6

Variant 1-158654738-G-T is Benign according to our data. Variant chr1-158654738-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 12846.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-158654738-G-T is described in Lovd as [Benign]. Variant chr1-158654738-G-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0333 (5063/152132) while in subpopulation NFE AF= 0.0489 (3322/67974). AF 95% confidence interval is 0.0475. There are 111 homozygotes in gnomad4. There are 2354 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 111 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPTA1	NM_003126.4 linkuse as main transcript	c.2909C>A	p.Ala970Asp	missense_variant	21/52	ENST00000643759.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPTA1	ENST00000643759.2 linkuse as main transcript	c.2909C>A	p.Ala970Asp	missense_variant	21/52		NM_003126.4	P1	P02549-1

Frequencies

GnomAD3 genomes

AF:

0.0333

AC:

5064

AN:

152014

Hom.:

111

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00879

Gnomad AMI

AF:

0.109

Gnomad AMR

AF:

0.0356

Gnomad ASJ

AF:

0.0577

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00748

Gnomad FIN

AF:

0.0386

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0489

Gnomad OTH

AF:

0.0407

GnomAD3 exomes

AF:

0.0330

AC:

8233

AN:

249336

Hom.:

173

AF XY:

0.0323

AC XY:

4375

AN XY:

135282

show subpopulations

Gnomad AFR exome

AF:

0.00775

Gnomad AMR exome

AF:

0.0226

Gnomad ASJ exome

AF:

0.0622

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00634

Gnomad FIN exome

AF:

0.0357

Gnomad NFE exome

AF:

0.0485

Gnomad OTH exome

AF:

0.0416

GnomAD4 exome

AF:

0.0422

AC:

61624

AN:

1461462

Hom.:

1476

Cov.:

AF XY:

0.0414

AC XY:

30075

AN XY:

727040

show subpopulations

Gnomad4 AFR exome

AF:

0.00615

Gnomad4 AMR exome

AF:

0.0252

Gnomad4 ASJ exome

AF:

0.0600

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00725

Gnomad4 FIN exome

AF:

0.0364

Gnomad4 NFE exome

AF:

0.0483

Gnomad4 OTH exome

AF:

0.0385

GnomAD4 genome

AF:

0.0333

AC:

5063

AN:

152132

Hom.:

111

Cov.:

AF XY:

0.0317

AC XY:

2354

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.00876

Gnomad4 AMR

AF:

0.0356

Gnomad4 ASJ

AF:

0.0577

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00769

Gnomad4 FIN

AF:

0.0386

Gnomad4 NFE

AF:

0.0489

Gnomad4 OTH

AF:

0.0402

Alfa

AF:

0.0446

Hom.:

295

Bravo

AF:

0.0329

TwinsUK

AF:

0.0448

AC:

166

ALSPAC

AF:

0.0524

AC:

202

ESP6500AA

AF:

0.00718

AC:

ESP6500EA

AF:

0.0497

AC:

413

ExAC

AF:

0.0327

AC:

3948

Asia WGS

AF:

0.00664

AC:

AN:

3478

EpiCase

AF:

0.0461

EpiControl

AF:

0.0484

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: frequency -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 18, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -

Spherocytosis, type 3, autosomal recessive

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 1993

- -

Pyropoikilocytosis, hereditary;C1851741:Elliptocytosis 2;C2678338:Hereditary spherocytosis type 3

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 29, 2021

- -

Hereditary spherocytosis type 3

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Pyropoikilocytosis, hereditary

Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.45

Cadd

Uncertain

Dann

Benign

0.97

DEOGEN2

Benign

0.22

T;T

Eigen

Benign

-0.22

Eigen_PC

Benign

0.000077

FATHMM_MKL

Benign

0.74

MetaRNN

Benign

0.0030

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

L;L

MutationTaster

Benign

0.97

A;A

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.73

N;.

REVEL

Benign

0.074

Sift

Benign

0.081

T;.

Sift4G

Uncertain

0.019

D;.

Polyphen

0.0010

B;B

Vest4

0.41

MPC

0.15

ClinPred

0.039

GERP RS

5.2

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

3.7

Varity_R

0.24

gMVP

0.28

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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