1-158617600-C-T

Variant names:

• chr1-158617600-C-T
• rs857716
• NM_003126.4:c.6549-12G>A

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.6549-12G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.539 in 1,603,432 control chromosomes in the GnomAD database, including 236,032 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (20422 hom., cov: 32)
  • Exomes 𝑓: 0.54 (215610 hom.)
• Consequence: SPTA1 NM_003126.4 intron
• Scores: Splicing: ADA: 0.0009544
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:13
• Conservation: PhyloP100: -1.69

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=-0.69).
• BP6: Variant 1-158617600-C-T is Benign according to our data. Variant chr1-158617600-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 258955.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-158617600-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.606 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPTA1	NM_003126.4	c.6549-12G>A		intron_variant	Intron 46 of 51	ENST00000643759.2	NP_003117.2
SPTA1	XM_011509916.3	c.6549-12G>A		intron_variant	Intron 47 of 52		XP_011508218.1
SPTA1	XM_011509917.4	c.6531-12G>A		intron_variant	Intron 45 of 50		XP_011508219.1
SPTA1	XM_047428883.1	c.6228-12G>A		intron_variant	Intron 46 of 51		XP_047284839.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPTA1	ENST00000643759.2	c.6549-12G>A		intron_variant	Intron 46 of 51		NM_003126.4	ENSP00000495214.1
SPTA1	ENST00000492934.1	n.64-12G>A		intron_variant	Intron 1 of 2	2
SPTA1	ENST00000498708.1	n.-32G>A		upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.510 AC: 77478 AN: 151854 Hom.: 20402 Cov.: 32

Gnomad AFR AF: 0.382

Gnomad AMI AF: 0.555

Gnomad AMR AF: 0.543

Gnomad ASJ AF: 0.578

Gnomad EAS AF: 0.624

Gnomad SAS AF: 0.431

Gnomad FIN AF: 0.640

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.553

Gnomad OTH AF: 0.533

GnomAD3 exomes AF: 0.538 AC: 133404 AN: 248152 Hom.: 36534 AF XY: 0.535 AC XY: 72086 AN XY: 134632

Gnomad AFR exome AF: 0.381

Gnomad AMR exome AF: 0.540

Gnomad ASJ exome AF: 0.585

Gnomad EAS exome AF: 0.608

Gnomad SAS exome AF: 0.429

Gnomad FIN exome AF: 0.634

Gnomad NFE exome AF: 0.553

Gnomad OTH exome AF: 0.547

GnomAD4 exome AF: 0.542 AC: 786672 AN: 1451460 Hom.: 215610 Cov.: 32 AF XY: 0.539 AC XY: 389653 AN XY: 722610

Gnomad4 AFR exome AF: 0.383

Gnomad4 AMR exome AF: 0.541

Gnomad4 ASJ exome AF: 0.583

Gnomad4 EAS exome AF: 0.606

Gnomad4 SAS exome AF: 0.428

Gnomad4 FIN exome AF: 0.630

Gnomad4 NFE exome AF: 0.548

Gnomad4 OTH exome AF: 0.544

GnomAD4 genome AF: 0.510 AC: 77549 AN: 151972 Hom.: 20422 Cov.: 32 AF XY: 0.516 AC XY: 38327 AN XY: 74266

Gnomad4 AFR AF: 0.382

Gnomad4 AMR AF: 0.543

Gnomad4 ASJ AF: 0.578

Gnomad4 EAS AF: 0.624

Gnomad4 SAS AF: 0.432

Gnomad4 FIN AF: 0.640

Gnomad4 NFE AF: 0.553

Gnomad4 OTH AF: 0.537

Alfa AF: 0.475 Hom.: 3898

Bravo AF: 0.501

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 01, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 32581362) -

Oct 31, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:3

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Elliptocytosis 2 Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary spherocytosis type 3 Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Pyropoikilocytosis, hereditary Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hemolytic anemia Pathogenic:1

-

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	3.8
DANN	Benign	0.65
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00095
dbscSNV1_RF	Benign	0.10
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: rs857716; hg19: chr1-158587390;