rs2518493

Positions:

• chr1-158661381-A-C
• chr1-158661381-A-G
• chr1-158661381-A-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.2493T>G​(p.Leu831=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.252 in 1,613,118 control chromosomes in the GnomAD database, including 53,395 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L831L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.24 (4651 hom., cov: 32)
  • Exomes 𝑓: 0.25 (48744 hom.)
• Consequence: SPTA1 NM_003126.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.0940

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=-0.58).
• BP6: Variant 1-158661381-A-C is Benign according to our data. Variant chr1-158661381-A-C is described in ClinVar as [Benign]. Clinvar id is 258922.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-158661381-A-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.094 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.42 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPTA1	NM_003126.4	c.2493T>G	p.Leu831=	synonymous_variant	18/52	ENST00000643759.2	NP_003117.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPTA1	ENST00000643759.2	c.2493T>G	p.Leu831=	synonymous_variant	18/52		NM_003126.4	ENSP00000495214	P1
SPTA1	ENST00000647256.1	n.93T>G		non_coding_transcript_exon_variant	1/3

Frequencies

GnomAD3 genomes AF: 0.241 AC: 36662 AN: 151910 Hom.: 4647 Cov.: 32

Gnomad AFR AF: 0.173

Gnomad AMI AF: 0.300

Gnomad AMR AF: 0.292

Gnomad ASJ AF: 0.227

Gnomad EAS AF: 0.435

Gnomad SAS AF: 0.160

Gnomad FIN AF: 0.324

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.249

Gnomad OTH AF: 0.250

GnomAD3 exomes AF: 0.268 AC: 66659 AN: 248986 Hom.: 9722 AF XY: 0.260 AC XY: 35134 AN XY: 135112

Gnomad AFR exome AF: 0.174

Gnomad AMR exome AF: 0.343

Gnomad ASJ exome AF: 0.222

Gnomad EAS exome AF: 0.425

Gnomad SAS exome AF: 0.154

Gnomad FIN exome AF: 0.339

Gnomad NFE exome AF: 0.254

Gnomad OTH exome AF: 0.265

GnomAD4 exome AF: 0.253 AC: 370287 AN: 1461090 Hom.: 48744 Cov.: 36 AF XY: 0.249 AC XY: 181204 AN XY: 726846

Gnomad4 AFR exome AF: 0.163

Gnomad4 AMR exome AF: 0.338

Gnomad4 ASJ exome AF: 0.220

Gnomad4 EAS exome AF: 0.381

Gnomad4 SAS exome AF: 0.157

Gnomad4 FIN exome AF: 0.336

Gnomad4 NFE exome AF: 0.252

Gnomad4 OTH exome AF: 0.261

GnomAD4 genome AF: 0.241 AC: 36698 AN: 152028 Hom.: 4651 Cov.: 32 AF XY: 0.245 AC XY: 18198 AN XY: 74296

Gnomad4 AFR AF: 0.173

Gnomad4 AMR AF: 0.293

Gnomad4 ASJ AF: 0.227

Gnomad4 EAS AF: 0.435

Gnomad4 SAS AF: 0.161

Gnomad4 FIN AF: 0.324

Gnomad4 NFE AF: 0.249

Gnomad4 OTH AF: 0.252

Alfa AF: 0.239 Hom.: 7450

Bravo AF: 0.243

Asia WGS AF: 0.313 AC: 1084 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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	- -

Elliptocytosis 2 Benign:1

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:1

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:1

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	-0.58
CADD	Benign	5.3
DANN	Benign	0.77
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: rs2518493; hg19: chr1-158631171; COSMIC: COSV63748244;