rs34973695

Variant summary

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

The NM_003126.4(SPTA1):c.4453C>T(p.Leu1485Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0233 in 1,613,524 control chromosomes in the GnomAD database, including 524 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.018 ( 39 hom., cov: 32)

Exomes 𝑓: 0.024 ( 485 hom. )

Consequence

SPTA1
NM_003126.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:4

Conservation

PhyloP100: 4.61

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=0.009739518).

BP6

Variant 1-158642966-G-A is Benign according to our data. Variant chr1-158642966-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 258938.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Benign=3, Likely_benign=1}. Variant chr1-158642966-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0176 (2677/152166) while in subpopulation SAS AF= 0.0281 (135/4806). AF 95% confidence interval is 0.0258. There are 39 homozygotes in gnomad4. There are 1271 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 39 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPTA1	NM_003126.4 linkuse as main transcript	c.4453C>T	p.Leu1485Phe	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.4453C>T	p.Leu1485Phe	missense_variant	32/52		NM_003126.4	P1	P02549-1

Frequencies

GnomAD3 genomes

AF:

0.0176

AC:

2674

AN:

152046

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00435

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0145

Gnomad ASJ

AF:

0.0406

Gnomad EAS

AF:

0.000964

Gnomad SAS

AF:

0.0274

Gnomad FIN

AF:

0.0126

Gnomad MID

AF:

0.0223

Gnomad NFE

AF:

0.0268

Gnomad OTH

AF:

0.0158

GnomAD3 exomes

AF:

0.0198

AC:

4933

AN:

248812

Hom.:

AF XY:

0.0212

AC XY:

2861

AN XY:

134950

show subpopulations

Gnomad AFR exome

AF:

0.00484

Gnomad AMR exome

AF:

0.0130

Gnomad ASJ exome

AF:

0.0331

Gnomad EAS exome

AF:

0.000167

Gnomad SAS exome

AF:

0.0274

Gnomad FIN exome

AF:

0.0127

Gnomad NFE exome

AF:

0.0252

Gnomad OTH exome

AF:

0.0204

GnomAD4 exome

AF:

0.0239

AC:

34963

AN:

1461358

Hom.:

485

Cov.:

AF XY:

0.0243

AC XY:

17630

AN XY:

726964

show subpopulations

Gnomad4 AFR exome

AF:

0.00290

Gnomad4 AMR exome

AF:

0.0142

Gnomad4 ASJ exome

AF:

0.0340

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0280

Gnomad4 FIN exome

AF:

0.0128

Gnomad4 NFE exome

AF:

0.0260

Gnomad4 OTH exome

AF:

0.0219

GnomAD4 genome

AF:

0.0176

AC:

2677

AN:

152166

Hom.:

Cov.:

AF XY:

0.0171

AC XY:

1271

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.00433

Gnomad4 AMR

AF:

0.0145

Gnomad4 ASJ

AF:

0.0406

Gnomad4 EAS

AF:

0.000966

Gnomad4 SAS

AF:

0.0281

Gnomad4 FIN

AF:

0.0126

Gnomad4 NFE

AF:

0.0268

Gnomad4 OTH

AF:

0.0156

Alfa

AF:

0.0245

Hom.:

Bravo

AF:

0.0173

TwinsUK

AF:

0.0235

AC:

ALSPAC

AF:

0.0249

AC:

ESP6500AA

AF:

0.00476

AC:

ESP6500EA

AF:

0.0247

AC:

206

ExAC

AF:

0.0194

AC:

2347

Asia WGS

AF:

0.0130

AC:

AN:

3478

EpiCase

AF:

0.0266

EpiControl

AF:

0.0272

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 16, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 08, 2023	BS1, BS2 -

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

Uncertain

0.35

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.18

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.53

D;D

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Uncertain

0.96

MetaRNN

Benign

0.0097

T;T

MetaSVM

Uncertain

0.23

MutationAssessor

Pathogenic

3.6

H;H

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.48

PROVEAN

Uncertain

-3.5

D;.

REVEL

Uncertain

0.53

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;.

Polyphen

1.0

D;D

Vest4

0.42

MPC

0.23

ClinPred

0.053

GERP RS

5.2

Varity_R

0.59

gMVP

0.30

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