rs3753068

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_003126.4(SPTA1):c.5958C>T(p.Pro1986=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.3 in 1,613,570 control chromosomes in the GnomAD database, including 74,567 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.33 ( 8710 hom., cov: 32)

Exomes 𝑓: 0.30 ( 65857 hom. )

Consequence

SPTA1
NM_003126.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.292

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.54).

BP6

Variant 1-158623145-G-A is Benign according to our data. Variant chr1-158623145-G-A is described in ClinVar as [Benign]. Clinvar id is 258949.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-158623145-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.292 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.422 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPTA1	NM_003126.4 linkuse as main transcript	c.5958C>T	p.Pro1986=	synonymous_variant	43/52	ENST00000643759.2	NP_003117.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPTA1	ENST00000643759.2 linkuse as main transcript	c.5958C>T	p.Pro1986=	synonymous_variant	43/52		NM_003126.4	ENSP00000495214	P1	P02549-1
SPTA1	ENST00000461624.1 linkuse as main transcript	n.504C>T		non_coding_transcript_exon_variant	5/5	2

Frequencies

GnomAD3 genomes

AF:

0.331

AC:

50216

AN:

151750

Hom.:

8699

Cov.:

show subpopulations

Gnomad AFR

AF:

0.427

Gnomad AMI

AF:

0.227

Gnomad AMR

AF:

0.255

Gnomad ASJ

AF:

0.392

Gnomad EAS

AF:

0.184

Gnomad SAS

AF:

0.291

Gnomad FIN

AF:

0.317

Gnomad MID

AF:

0.399

Gnomad NFE

AF:

0.304

Gnomad OTH

AF:

0.325

GnomAD3 exomes

AF:

0.290

AC:

72332

AN:

249348

Hom.:

11013

AF XY:

0.293

AC XY:

39637

AN XY:

135274

show subpopulations

Gnomad AFR exome

AF:

0.430

Gnomad AMR exome

AF:

0.197

Gnomad ASJ exome

AF:

0.401

Gnomad EAS exome

AF:

0.186

Gnomad SAS exome

AF:

0.301

Gnomad FIN exome

AF:

0.300

Gnomad NFE exome

AF:

0.301

Gnomad OTH exome

AF:

0.292

GnomAD4 exome

AF:

0.297

AC:

433639

AN:

1461702

Hom.:

65857

Cov.:

AF XY:

0.298

AC XY:

216462

AN XY:

727160

show subpopulations

Gnomad4 AFR exome

AF:

0.436

Gnomad4 AMR exome

AF:

0.203

Gnomad4 ASJ exome

AF:

0.403

Gnomad4 EAS exome

AF:

0.203

Gnomad4 SAS exome

AF:

0.300

Gnomad4 FIN exome

AF:

0.299

Gnomad4 NFE exome

AF:

0.296

Gnomad4 OTH exome

AF:

0.300

GnomAD4 genome

AF:

0.331

AC:

50268

AN:

151868

Hom.:

8710

Cov.:

AF XY:

0.331

AC XY:

24583

AN XY:

74210

show subpopulations

Gnomad4 AFR

AF:

0.427

Gnomad4 AMR

AF:

0.255

Gnomad4 ASJ

AF:

0.392

Gnomad4 EAS

AF:

0.185

Gnomad4 SAS

AF:

0.290

Gnomad4 FIN

AF:

0.317

Gnomad4 NFE

AF:

0.304

Gnomad4 OTH

AF:

0.327

Alfa

AF:

0.306

Hom.:

3877

Bravo

AF:

0.329

Asia WGS

AF:

0.245

AC:

852

AN:

3478

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

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Elliptocytosis 2

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. -

Hereditary spherocytosis type 3

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. -

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

BayesDel_noAF

Benign

-0.54

CADD

Benign

0.56

DANN

Benign

0.48

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