rs325995

chr1-158677841-T-Achr1-158677841-T-G

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.813-7A>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.99 in 1,613,432 control chromosomes in the GnomAD database, including 791,166 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.96 (70103 hom., cov: 31)
  • Exomes 𝑓: 0.99 (721063 hom.)
• Consequence: SPTA1 NM_003126.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001651
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 3.34

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=-0.83).
• BP6: Variant 1-158677841-T-A is Benign according to our data. Variant chr1-158677841-T-A is described in ClinVar as [Benign]. Clinvar id is 258959.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-158677841-T-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.991 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPTA1	NM_003126.4	c.813-7A>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000643759.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPTA1	ENST00000643759.2	c.813-7A>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_003126.4	P1

Frequencies

GnomAD3 genomes AF: 0.958 AC: 145688 AN: 152044 Hom.: 70051 Cov.: 31

Gnomad AFR AF: 0.864

Gnomad AMI AF: 0.970

Gnomad AMR AF: 0.984

Gnomad ASJ AF: 0.998

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.998

Gnomad FIN AF: 0.983

Gnomad MID AF: 0.987

Gnomad NFE AF: 0.997

Gnomad OTH AF: 0.968

GnomAD3 exomes AF: 0.987 AC: 245553 AN: 248822 Hom.: 121297 AF XY: 0.989 AC XY: 133546 AN XY: 134978

Gnomad AFR exome AF: 0.858

Gnomad AMR exome AF: 0.992

Gnomad ASJ exome AF: 0.999

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 0.999

Gnomad FIN exome AF: 0.985

Gnomad NFE exome AF: 0.996

Gnomad OTH exome AF: 0.993

GnomAD4 exome AF: 0.993 AC: 1451333 AN: 1461270 Hom.: 721063 Cov.: 57 AF XY: 0.994 AC XY: 722476 AN XY: 726954

Gnomad4 AFR exome AF: 0.862

Gnomad4 AMR exome AF: 0.990

Gnomad4 ASJ exome AF: 0.999

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.999

Gnomad4 FIN exome AF: 0.986

Gnomad4 NFE exome AF: 0.997

Gnomad4 OTH exome AF: 0.988

GnomAD4 genome AF: 0.958 AC: 145797 AN: 152162 Hom.: 70103 Cov.: 31 AF XY: 0.960 AC XY: 71410 AN XY: 74376

Gnomad4 AFR AF: 0.864

Gnomad4 AMR AF: 0.984

Gnomad4 ASJ AF: 0.998

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.998

Gnomad4 FIN AF: 0.983

Gnomad4 NFE AF: 0.997

Gnomad4 OTH AF: 0.969

Alfa AF: 0.990 Hom.: 18958

Bravo AF: 0.954

Asia WGS AF: 0.993 AC: 3453 AN: 3478

EpiCase AF: 0.998

EpiControl AF: 0.998

ClinVar

Significance: Benign

Submissions summary: Benign:12

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	GeneDx	Jun 09, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -

Elliptocytosis 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
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:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
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:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
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	-0.83
Cadd	Benign	7.8
Dann	Benign	0.49
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000017
dbscSNV1_RF	Benign	0.0020
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: rs325995; hg19: chr1-158647631;