1-158656588-C-T

Position:

• chr1-158656588-C-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.2874G>A​(p.Leu958Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.28 in 1,612,524 control chromosomes in the GnomAD database, including 73,055 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (14880 hom., cov: 32)
  • Exomes 𝑓: 0.27 (58175 hom.)
• Consequence: SPTA1 NM_003126.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.754

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 1-158656588-C-T is Benign according to our data. Variant chr1-158656588-C-T is described in ClinVar as [Benign]. Clinvar id is 258926.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-158656588-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.754 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.699 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPTA1	NM_003126.4	c.2874G>A	p.Leu958Leu	synonymous_variant	20/52	ENST00000643759.2	NP_003117.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPTA1	ENST00000643759.2	c.2874G>A	p.Leu958Leu	synonymous_variant	20/52		NM_003126.4	ENSP00000495214.1
SPTA1	ENST00000647256.1	n.*43G>A		downstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.394 AC: 59904 AN: 151940 Hom.: 14839 Cov.: 32

Gnomad AFR AF: 0.706

Gnomad AMI AF: 0.300

Gnomad AMR AF: 0.353

Gnomad ASJ AF: 0.244

Gnomad EAS AF: 0.435

Gnomad SAS AF: 0.167

Gnomad FIN AF: 0.320

Gnomad MID AF: 0.293

Gnomad NFE AF: 0.249

Gnomad OTH AF: 0.359

GnomAD3 exomes AF: 0.307 AC: 76446 AN: 249068 Hom.: 13994 AF XY: 0.290 AC XY: 39134 AN XY: 135134

Gnomad AFR exome AF: 0.721

Gnomad AMR exome AF: 0.372

Gnomad ASJ exome AF: 0.238

Gnomad EAS exome AF: 0.425

Gnomad SAS exome AF: 0.157

Gnomad FIN exome AF: 0.335

Gnomad NFE exome AF: 0.254

Gnomad OTH exome AF: 0.287

GnomAD4 exome AF: 0.268 AC: 391598 AN: 1460466 Hom.: 58175 Cov.: 33 AF XY: 0.262 AC XY: 190323 AN XY: 726582

Gnomad4 AFR exome AF: 0.722

Gnomad4 AMR exome AF: 0.370

Gnomad4 ASJ exome AF: 0.236

Gnomad4 EAS exome AF: 0.381

Gnomad4 SAS exome AF: 0.160

Gnomad4 FIN exome AF: 0.332

Gnomad4 NFE exome AF: 0.251

Gnomad4 OTH exome AF: 0.300

GnomAD4 genome AF: 0.395 AC: 60010 AN: 152058 Hom.: 14880 Cov.: 32 AF XY: 0.394 AC XY: 29265 AN XY: 74314

Gnomad4 AFR AF: 0.706

Gnomad4 AMR AF: 0.353

Gnomad4 ASJ AF: 0.244

Gnomad4 EAS AF: 0.435

Gnomad4 SAS AF: 0.167

Gnomad4 FIN AF: 0.320

Gnomad4 NFE AF: 0.249

Gnomad4 OTH AF: 0.361

Alfa AF: 0.268 Hom.: 13559

Bravo AF: 0.416

Asia WGS AF: 0.358 AC: 1242 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

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	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 24, 2021	- -

not specified Benign:3

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	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

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. -

Hereditary spherocytosis type 3 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. -

Pyropoikilocytosis, hereditary 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.084
DANN	Benign	0.43
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs857691; hg19: chr1-158626378; COSMIC: COSV63748240; COSMIC: COSV63748240;