rs77877855

chr1-158623111-C-Gchr1-158623111-C-T

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.5992G>C(p.Ala1998Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0235 in 1,613,978 control chromosomes in the GnomAD database, including 1,310 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.053 (491 hom., cov: 32)
  • Exomes 𝑓: 0.020 (819 hom.)
• Consequence: SPTA1 NM_003126.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 3.79

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 (MetaRNN=0.0021986663).
• BP6: Variant 1-158623111-C-G is Benign according to our data. Variant chr1-158623111-C-G is described in ClinVar as [Benign]. Clinvar id is 258950.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-158623111-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.143 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPTA1	NM_003126.4	c.5992G>C	p.Ala1998Pro	missense_variant	43/52	ENST00000643759.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPTA1	ENST00000643759.2	c.5992G>C	p.Ala1998Pro	missense_variant	43/52		NM_003126.4	P1
SPTA1	ENST00000461624.1	n.538G>C		non_coding_transcript_exon_variant	5/5	2

Frequencies

GnomAD3 genomes AF: 0.0531 AC: 8078 AN: 152102 Hom.: 489 Cov.: 32

Gnomad AFR AF: 0.145

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0268

Gnomad ASJ AF: 0.0495

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0456

Gnomad FIN AF: 0.00885

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0153

Gnomad OTH AF: 0.0479

GnomAD3 exomes AF: 0.0292 AC: 7273 AN: 249460 Hom.: 274 AF XY: 0.0291 AC XY: 3936 AN XY: 135334

Gnomad AFR exome AF: 0.145

Gnomad AMR exome AF: 0.0198

Gnomad ASJ exome AF: 0.0518

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: 29881 AN: 1461758 Hom.: 819 Cov.: 30 AF XY: 0.0212 AC XY: 15442 AN XY: 727186

Gnomad4 AFR exome AF: 0.147

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: 0.0293

GnomAD4 genome AF: 0.0533 AC: 8110 AN: 152220 Hom.: 491 Cov.: 32 AF XY: 0.0526 AC XY: 3915 AN XY: 74418

Gnomad4 AFR AF: 0.146

Gnomad4 AMR AF: 0.0267

Gnomad4 ASJ AF: 0.0495

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0455

Gnomad4 FIN AF: 0.00885

Gnomad4 NFE AF: 0.0153

Gnomad4 OTH AF: 0.0474

Alfa AF: 0.0185 Hom.: 59

Bravo AF: 0.0585

TwinsUK AF: 0.0135 AC: 50

ALSPAC AF: 0.0145 AC: 56

ESP6500AA AF: 0.141 AC: 550

ESP6500EA AF: 0.0152 AC: 126

ExAC AF: 0.0317 AC: 3833

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	GeneDx	Feb 04, 2020	This variant is associated with the following publications: (PMID: 27884173, 24193021) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 16, 2023	- -

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
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	19
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D;D
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.95	D
MetaRNN	Benign	0.0022	T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Uncertain	2.8	M;M
MutationTaster	Benign	0.89	D;D
PrimateAI	Benign	0.38	T
REVEL	Benign	0.25
Sift4G	Uncertain	0.0040	D;.
Polyphen		0.96	D;D
Vest4		0.47
MPC		0.20
ClinPred		0.017	T
GERP RS		3.9
Varity_R		0.77
gMVP		0.40

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: rs77877855; hg19: chr1-158592901;