rs75931146

chr1-158622991-G-A

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.6112C>T(p.Leu2038=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0235 in 1,613,796 control chromosomes in the GnomAD database, including 1,304 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.053 (486 hom., cov: 32)
  • Exomes 𝑓: 0.020 (818 hom.)
• Consequence: SPTA1 NM_003126.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 3.47

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=-0.53).
• BP6: Variant 1-158622991-G-A is Benign according to our data. Variant chr1-158622991-G-A is described in ClinVar as [Benign]. Clinvar id is 258952.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-158622991-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=3.47 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.142 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPTA1	NM_003126.4	c.6112C>T	p.Leu2038=	synonymous_variant	43/52	ENST00000643759.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPTA1	ENST00000643759.2	c.6112C>T	p.Leu2038=	synonymous_variant	43/52		NM_003126.4	P1
SPTA1	ENST00000461624.1	n.658C>T		non_coding_transcript_exon_variant	5/5	2

Frequencies

GnomAD3 genomes AF: 0.0530 AC: 8067 AN: 152072 Hom.: 484 Cov.: 32

Gnomad AFR AF: 0.145

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0266

Gnomad ASJ AF: 0.0496

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0463

Gnomad FIN AF: 0.00868

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0153

Gnomad OTH AF: 0.0483

GnomAD3 exomes AF: 0.0291 AC: 7267 AN: 249532 Hom.: 274 AF XY: 0.0291 AC XY: 3936 AN XY: 135380

Gnomad AFR exome AF: 0.144

Gnomad AMR exome AF: 0.0198

Gnomad ASJ exome AF: 0.0517

Gnomad EAS exome AF: 0.000278

Gnomad SAS exome AF: 0.0501

Gnomad FIN exome AF: 0.00812

Gnomad NFE exome AF: 0.0171

Gnomad OTH exome AF: 0.0297

GnomAD4 exome AF: 0.0204 AC: 29857 AN: 1461606 Hom.: 818 Cov.: 30 AF XY: 0.0212 AC XY: 15430 AN XY: 727124

Gnomad4 AFR exome AF: 0.146

Gnomad4 AMR exome AF: 0.0209

Gnomad4 ASJ exome AF: 0.0528

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0539

Gnomad4 FIN exome AF: 0.00929

Gnomad4 NFE exome AF: 0.0137

Gnomad4 OTH exome AF: 0.0292

GnomAD4 genome AF: 0.0532 AC: 8099 AN: 152190 Hom.: 486 Cov.: 32 AF XY: 0.0527 AC XY: 3918 AN XY: 74404

Gnomad4 AFR AF: 0.146

Gnomad4 AMR AF: 0.0265

Gnomad4 ASJ AF: 0.0496

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0461

Gnomad4 FIN AF: 0.00868

Gnomad4 NFE AF: 0.0153

Gnomad4 OTH AF: 0.0478

Alfa AF: 0.0334 Hom.: 118

Bravo AF: 0.0583

Asia WGS AF: 0.0290 AC: 100 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 16, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

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	-0.53
Cadd	Benign	0.69
Dann	Benign	0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs75931146; hg19: chr1-158592781;