rs2246434

Positions:

• chr1-158648665-G-A
• chr1-158648665-G-C

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.3570-12C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.247 in 1,612,600 control chromosomes in the GnomAD database, including 51,402 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4285 hom., cov: 30)
  • Exomes 𝑓: 0.25 (47117 hom.)
• Consequence: SPTA1 NM_003126.4 intron
• Scores: Splicing: ADA: 0.00001248
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.161

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 1-158648665-G-A is Benign according to our data. Variant chr1-158648665-G-A is described in ClinVar as [Benign]. Clinvar id is 258930.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-158648665-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.411 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPTA1	NM_003126.4	c.3570-12C>T		intron_variant		ENST00000643759.2	NP_003117.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPTA1	ENST00000643759.2	c.3570-12C>T		intron_variant			NM_003126.4	ENSP00000495214.1

Frequencies

GnomAD3 genomes AF: 0.224 AC: 34069 AN: 151760 Hom.: 4278 Cov.: 30

Gnomad AFR AF: 0.124

Gnomad AMI AF: 0.298

Gnomad AMR AF: 0.283

Gnomad ASJ AF: 0.220

Gnomad EAS AF: 0.426

Gnomad SAS AF: 0.159

Gnomad FIN AF: 0.321

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.246

Gnomad OTH AF: 0.232

GnomAD3 exomes AF: 0.260 AC: 64575 AN: 248566 Hom.: 9183 AF XY: 0.254 AC XY: 34205 AN XY: 134880

Gnomad AFR exome AF: 0.118

Gnomad AMR exome AF: 0.336

Gnomad ASJ exome AF: 0.213

Gnomad EAS exome AF: 0.409

Gnomad SAS exome AF: 0.153

Gnomad FIN exome AF: 0.337

Gnomad NFE exome AF: 0.251

Gnomad OTH exome AF: 0.258

GnomAD4 exome AF: 0.249 AC: 363879 AN: 1460720 Hom.: 47117 Cov.: 39 AF XY: 0.245 AC XY: 178404 AN XY: 726698

Gnomad4 AFR exome AF: 0.115

Gnomad4 AMR exome AF: 0.331

Gnomad4 ASJ exome AF: 0.212

Gnomad4 EAS exome AF: 0.368

Gnomad4 SAS exome AF: 0.156

Gnomad4 FIN exome AF: 0.333

Gnomad4 NFE exome AF: 0.250

Gnomad4 OTH exome AF: 0.255

GnomAD4 genome AF: 0.225 AC: 34107 AN: 151880 Hom.: 4285 Cov.: 30 AF XY: 0.229 AC XY: 17028 AN XY: 74236

Gnomad4 AFR AF: 0.125

Gnomad4 AMR AF: 0.284

Gnomad4 ASJ AF: 0.220

Gnomad4 EAS AF: 0.426

Gnomad4 SAS AF: 0.159

Gnomad4 FIN AF: 0.321

Gnomad4 NFE AF: 0.246

Gnomad4 OTH AF: 0.234

Alfa AF: 0.241 Hom.: 4823

Bravo AF: 0.222

Asia WGS AF: 0.319 AC: 1108 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:9

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	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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 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	-0.82
CADD	Benign	0.88
DANN	Benign	0.47

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000012
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.010		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: rs2246434; hg19: chr1-158618455; COSMIC: COSV63755347;