rs41273523

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_003126.4(SPTA1):c.4490G>A(p.Gly1497Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0157 in 1,613,718 control chromosomes in the GnomAD database, including 230 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.013 ( 19 hom., cov: 32)

Exomes 𝑓: 0.016 ( 211 hom. )

Consequence

SPTA1
NM_003126.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:6

Conservation

PhyloP100: 4.75

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0053780377).

BP6

Variant 1-158642929-C-T is Benign according to our data. Variant chr1-158642929-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 258940.We mark this variant Likely_benign, oryginal submissions are: {Benign=5, Likely_benign=1, Uncertain_significance=3}. Variant chr1-158642929-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0129 (1959/152178) while in subpopulation NFE AF= 0.0189 (1285/67998). AF 95% confidence interval is 0.018. There are 19 homozygotes in gnomad4. There are 985 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 19 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPTA1	NM_003126.4 linkuse as main transcript	c.4490G>A	p.Gly1497Glu	missense_variant	32/52	ENST00000643759.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPTA1	ENST00000643759.2 linkuse as main transcript	c.4490G>A	p.Gly1497Glu	missense_variant	32/52		NM_003126.4	P1	P02549-1

Frequencies

GnomAD3 genomes

AF:

0.0129

AC:

1958

AN:

152060

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00299

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.00793

Gnomad ASJ

AF:

0.00922

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00187

Gnomad FIN

AF:

0.0337

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0189

Gnomad OTH

AF:

0.0100

GnomAD3 exomes

AF:

0.0140

AC:

3496

AN:

249130

Hom.:

AF XY:

0.0142

AC XY:

1916

AN XY:

135148

show subpopulations

Gnomad AFR exome

AF:

0.00258

Gnomad AMR exome

AF:

0.00723

Gnomad ASJ exome

AF:

0.0144

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00284

Gnomad FIN exome

AF:

0.0318

Gnomad NFE exome

AF:

0.0194

Gnomad OTH exome

AF:

0.0170

GnomAD4 exome

AF:

0.0160

AC:

23330

AN:

1461540

Hom.:

211

Cov.:

AF XY:

0.0157

AC XY:

11412

AN XY:

727070

show subpopulations

Gnomad4 AFR exome

AF:

0.00206

Gnomad4 AMR exome

AF:

0.00707

Gnomad4 ASJ exome

AF:

0.0147

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00319

Gnomad4 FIN exome

AF:

0.0303

Gnomad4 NFE exome

AF:

0.0178

Gnomad4 OTH exome

AF:

0.0139

GnomAD4 genome

AF:

0.0129

AC:

1959

AN:

152178

Hom.:

Cov.:

AF XY:

0.0132

AC XY:

985

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.00299

Gnomad4 AMR

AF:

0.00792

Gnomad4 ASJ

AF:

0.00922

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00208

Gnomad4 FIN

AF:

0.0337

Gnomad4 NFE

AF:

0.0189

Gnomad4 OTH

AF:

0.00992

Alfa

AF:

0.0173

Hom.:

Bravo

AF:

0.0107

TwinsUK

AF:

0.0189

AC:

ALSPAC

AF:

0.0114

AC:

ESP6500AA

AF:

0.00376

AC:

ESP6500EA

AF:

0.0170

AC:

142

ExAC

AF:

0.0145

AC:

1756

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.0206

EpiControl

AF:

0.0180

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 10, 2021	This variant is associated with the following publications: (PMID: 29396846) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	SPTA1: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 22, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 20, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 13, 2024	- -

Hereditary spherocytosis type 3

Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Pyropoikilocytosis, hereditary

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Elliptocytosis 2

Benign:1

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. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.65

Cadd

Benign

Dann

Benign

0.78

DEOGEN2

Uncertain

0.49

T;T

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.78

FATHMM_MKL

Uncertain

0.92

MetaRNN

Benign

0.0054

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.1

L;L

MutationTaster

Benign

0.98

N;N

PrimateAI

Benign

0.47

PROVEAN

Pathogenic

-5.8

D;.

REVEL

Benign

0.14

Sift

Benign

0.064

T;.

Sift4G

Benign

0.26

T;.

Polyphen

0.35

B;B

Vest4

0.23

MPC

0.075

ClinPred

0.075

GERP RS

0.0036

Varity_R

0.34

gMVP

0.14

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