rs3753068

chr1-158623145-G-Achr1-158623145-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.292

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]

ACMG classification

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	UniProt
SPTA1	NM_003126.4	c.5958C>T	p.Pro1986=	synonymous_variant	43/52	ENST00000643759.2

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.331 AC: 50216 AN: 151750 Hom.: 8699 Cov.: 32

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

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.: 38 AF XY: 0.298 AC XY: 216462 AN XY: 727160

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.: 32 AF XY: 0.331 AC XY: 24583 AN XY: 74210

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:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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

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. -

not provided Benign:2

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	- -

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

Other links and lift over

dbSNP: rs3753068; hg19: chr1-158592935; COSMIC: COSV63748986; COSMIC: COSV63748986;