1-158627717-G-C

Position:

• chr1-158627717-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_003126.4(SPTA1):​c.5572C>G​(p.Leu1858Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.271 in 1,609,240 control chromosomes in the GnomAD database, including 60,931 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.25 (5114 hom., cov: 32)
  • Exomes 𝑓: 0.27 (55817 hom.)
• Consequence: SPTA1 NM_003126.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 B:13
• Conservation: PhyloP100: 2.72

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018082857).
• BP6: Variant 1-158627717-G-C is Benign according to our data. Variant chr1-158627717-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 258948.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Pathogenic=1, Benign=9, Likely_pathogenic=1}. Variant chr1-158627717-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.285 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPTA1	NM_003126.4	c.5572C>G	p.Leu1858Val	missense_variant	40/52	ENST00000643759.2	NP_003117.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPTA1	ENST00000643759.2	c.5572C>G	p.Leu1858Val	missense_variant	40/52		NM_003126.4	ENSP00000495214.1
SPTA1	ENST00000461624.1	n.118C>G		non_coding_transcript_exon_variant	2/5	2

Frequencies

GnomAD3 genomes AF: 0.254 AC: 38547 AN: 151894 Hom.: 5113 Cov.: 32

Gnomad AFR AF: 0.198

Gnomad AMI AF: 0.229

Gnomad AMR AF: 0.218

Gnomad ASJ AF: 0.343

Gnomad EAS AF: 0.184

Gnomad SAS AF: 0.244

Gnomad FIN AF: 0.309

Gnomad MID AF: 0.321

Gnomad NFE AF: 0.288

Gnomad OTH AF: 0.259

GnomAD3 exomes AF: 0.255 AC: 63178 AN: 248208 Hom.: 8392 AF XY: 0.259 AC XY: 34938 AN XY: 134796

Gnomad AFR exome AF: 0.198

Gnomad AMR exome AF: 0.171

Gnomad ASJ exome AF: 0.350

Gnomad EAS exome AF: 0.186

Gnomad SAS exome AF: 0.250

Gnomad FIN exome AF: 0.292

Gnomad NFE exome AF: 0.284

Gnomad OTH exome AF: 0.261

GnomAD4 exome AF: 0.273 AC: 397913 AN: 1457228 Hom.: 55817 Cov.: 33 AF XY: 0.274 AC XY: 198451 AN XY: 725124

Gnomad4 AFR exome AF: 0.198

Gnomad4 AMR exome AF: 0.176

Gnomad4 ASJ exome AF: 0.351

Gnomad4 EAS exome AF: 0.203

Gnomad4 SAS exome AF: 0.246

Gnomad4 FIN exome AF: 0.289

Gnomad4 NFE exome AF: 0.282

Gnomad4 OTH exome AF: 0.265

GnomAD4 genome AF: 0.254 AC: 38556 AN: 152012 Hom.: 5114 Cov.: 32 AF XY: 0.255 AC XY: 18949 AN XY: 74296

Gnomad4 AFR AF: 0.198

Gnomad4 AMR AF: 0.218

Gnomad4 ASJ AF: 0.343

Gnomad4 EAS AF: 0.185

Gnomad4 SAS AF: 0.244

Gnomad4 FIN AF: 0.309

Gnomad4 NFE AF: 0.288

Gnomad4 OTH AF: 0.262

Alfa AF: 0.283 Hom.: 1175

Bravo AF: 0.242

TwinsUK AF: 0.276 AC: 1024

ALSPAC AF: 0.284 AC: 1093

ESP6500AA AF: 0.192 AC: 710

ESP6500EA AF: 0.276 AC: 2255

ExAC AF: 0.256 AC: 30969

Asia WGS AF: 0.209 AC: 729 AN: 3478

EpiCase AF: 0.283

EpiControl AF: 0.280

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Benign:13

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 28, 2021	Commonly referred to as the AlphaLELY allele when is cis with c.6531-12C>T, a low expression allele that results in partial skipping of exon 46 and expression of hereditary elliptocytosis when in trans with a pathogenic SPTA1 variant (Wilmotte et al., 1999); Observed with c.6531-12C>T multiple times with a variant on the opposite allele (in trans) in unrelated patients with hereditary pyropoikilocytosis or hereditary elliptocytosis in the published literature; is reported to result in more severe disease when in trans with a pathogenic variant (Niss et al., 2016; Ma et al., 2018; Aggarwal et al., 2020); This variant is associated with the following publications: (PMID: 32287101, 32581362, 31602632, 10192450) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2021	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:4

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	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 15, 2018	- -

Elliptocytosis 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

Hereditary spherocytosis type 3 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

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 12, 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. -

Hemolytic anemia Pathogenic:1

Likely pathogenic, flagged submission

research

NIHR Bioresource Rare Diseases, University of Cambridge

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.40	T;T
Eigen	Benign	-0.088
Eigen_PC	Benign	-0.10
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	.;D
MetaRNN	Benign	0.0018	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.7	M;M
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-2.4	N;.
REVEL	Benign	0.18
Sift	Uncertain	0.0090	D;.
Sift4G	Uncertain	0.019	D;.
Polyphen		0.60	P;P
Vest4		0.24
MPC		0.15
ClinPred		0.027	T
GERP RS		2.7
Varity_R		0.47
gMVP		0.10

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: rs3737515; hg19: chr1-158597507; COSMIC: COSV63752283;