rs703116

Positions:

• chr1-158674315-T-A
• chr1-158674315-T-C
• chr1-158674315-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003126.4(SPTA1):​c.1350+14A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.397 in 1,611,594 control chromosomes in the GnomAD database, including 131,090 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (9429 hom., cov: 32)
  • Exomes 𝑓: 0.40 (121661 hom.)
• Consequence: SPTA1 NM_003126.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.806

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 1-158674315-T-A is Benign according to our data. Variant chr1-158674315-T-A is described in ClinVar as [Benign]. Clinvar id is 258917.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-158674315-T-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.529 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPTA1	NM_003126.4	c.1350+14A>T		intron_variant		ENST00000643759.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPTA1	ENST00000643759.2	c.1350+14A>T		intron_variant			NM_003126.4	P1

Frequencies

GnomAD3 genomes AF: 0.330 AC: 50229 AN: 151988 Hom.: 9435 Cov.: 32

Gnomad AFR AF: 0.139

Gnomad AMI AF: 0.511

Gnomad AMR AF: 0.389

Gnomad ASJ AF: 0.420

Gnomad EAS AF: 0.430

Gnomad SAS AF: 0.547

Gnomad FIN AF: 0.354

Gnomad MID AF: 0.405

Gnomad NFE AF: 0.400

Gnomad OTH AF: 0.343

GnomAD3 exomes AF: 0.403 AC: 100403 AN: 249060 Hom.: 21327 AF XY: 0.412 AC XY: 55661 AN XY: 135136

Gnomad AFR exome AF: 0.130

Gnomad AMR exome AF: 0.423

Gnomad ASJ exome AF: 0.418

Gnomad EAS exome AF: 0.449

Gnomad SAS exome AF: 0.537

Gnomad FIN exome AF: 0.355

Gnomad NFE exome AF: 0.399

Gnomad OTH exome AF: 0.400

GnomAD4 exome AF: 0.404 AC: 589029 AN: 1459488 Hom.: 121661 Cov.: 32 AF XY: 0.409 AC XY: 296681 AN XY: 726244

Gnomad4 AFR exome AF: 0.129

Gnomad4 AMR exome AF: 0.416

Gnomad4 ASJ exome AF: 0.422

Gnomad4 EAS exome AF: 0.454

Gnomad4 SAS exome AF: 0.535

Gnomad4 FIN exome AF: 0.353

Gnomad4 NFE exome AF: 0.402

Gnomad4 OTH exome AF: 0.388

GnomAD4 genome AF: 0.330 AC: 50231 AN: 152106 Hom.: 9429 Cov.: 32 AF XY: 0.333 AC XY: 24724 AN XY: 74338

Gnomad4 AFR AF: 0.139

Gnomad4 AMR AF: 0.389

Gnomad4 ASJ AF: 0.420

Gnomad4 EAS AF: 0.430

Gnomad4 SAS AF: 0.546

Gnomad4 FIN AF: 0.354

Gnomad4 NFE AF: 0.400

Gnomad4 OTH AF: 0.342

Alfa AF: 0.357 Hom.: 1863

Bravo AF: 0.322

Asia WGS AF: 0.430 AC: 1497 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

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, 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	GeneDx	Nov 12, 2018	- -
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	- -

Elliptocytosis 2 Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

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	-0.80
CADD	Benign	2.8
DANN	Benign	0.45

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: rs703116; hg19: chr1-158644105; COSMIC: COSV63749143;