1-158638145-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.5077A>C(p.Lys1693Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.265 in 1,613,752 control chromosomes in the GnomAD database, including 59,409 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (4874 hom., cov: 32)
  • Exomes 𝑓: 0.27 (54535 hom.)
• Consequence: SPTA1 NM_003126.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.0140

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=4.7916174E-4).
• BP6: Variant 1-158638145-T-G is Benign according to our data. Variant chr1-158638145-T-G is described in ClinVar as [Benign]. Clinvar id is 258943.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-158638145-T-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.437 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPTA1	NM_003126.4	c.5077A>C	p.Lys1693Gln	missense_variant	36/52	ENST00000643759.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPTA1	ENST00000643759.2	c.5077A>C	p.Lys1693Gln	missense_variant	36/52		NM_003126.4	P1

Frequencies

GnomAD3 genomes AF: 0.239 AC: 36294 AN: 152018 Hom.: 4864 Cov.: 32

Gnomad AFR AF: 0.121

Gnomad AMI AF: 0.325

Gnomad AMR AF: 0.316

Gnomad ASJ AF: 0.236

Gnomad EAS AF: 0.452

Gnomad SAS AF: 0.185

Gnomad FIN AF: 0.329

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.265

Gnomad OTH AF: 0.259

GnomAD3 exomes AF: 0.280 AC: 69723 AN: 249014 Hom.: 10680 AF XY: 0.275 AC XY: 37091 AN XY: 135102

Gnomad AFR exome AF: 0.119

Gnomad AMR exome AF: 0.363

Gnomad ASJ exome AF: 0.237

Gnomad EAS exome AF: 0.434

Gnomad SAS exome AF: 0.179

Gnomad FIN exome AF: 0.344

Gnomad NFE exome AF: 0.271

Gnomad OTH exome AF: 0.285

GnomAD4 exome AF: 0.268 AC: 391943 AN: 1461616 Hom.: 54535 Cov.: 42 AF XY: 0.265 AC XY: 192648 AN XY: 727114

Gnomad4 AFR exome AF: 0.119

Gnomad4 AMR exome AF: 0.359

Gnomad4 ASJ exome AF: 0.235

Gnomad4 EAS exome AF: 0.408

Gnomad4 SAS exome AF: 0.182

Gnomad4 FIN exome AF: 0.340

Gnomad4 NFE exome AF: 0.268

Gnomad4 OTH exome AF: 0.276

GnomAD4 genome AF: 0.239 AC: 36344 AN: 152136 Hom.: 4874 Cov.: 32 AF XY: 0.243 AC XY: 18101 AN XY: 74364

Gnomad4 AFR AF: 0.121

Gnomad4 AMR AF: 0.316

Gnomad4 ASJ AF: 0.236

Gnomad4 EAS AF: 0.452

Gnomad4 SAS AF: 0.186

Gnomad4 FIN AF: 0.329

Gnomad4 NFE AF: 0.265

Gnomad4 OTH AF: 0.261

Alfa AF: 0.264 Hom.: 13810

Bravo AF: 0.238

TwinsUK AF: 0.268 AC: 995

ALSPAC AF: 0.260 AC: 1002

ESP6500AA AF: 0.123 AC: 467

ESP6500EA AF: 0.262 AC: 2159

ExAC AF: 0.273 AC: 33025

Asia WGS AF: 0.347 AC: 1202 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

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:2

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:1

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. -

Hereditary spherocytosis type 3 Benign:1

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. -

Pyropoikilocytosis, hereditary Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.80
Cadd	Benign	0.034
Dann	Benign	0.50
DEOGEN2	Benign	0.17	T;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.10	N
MetaRNN	Benign	0.00048	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N;N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.74	N;.
REVEL	Benign	0.013
Sift	Benign	0.26	T;.
Sift4G	Uncertain	0.048	D;.
Polyphen		0.0	B;B
Vest4		0.053
MPC		0.029
ClinPred		0.0070	T
GERP RS		-5.4
Varity_R		0.28
gMVP		0.061

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: rs857725; hg19: chr1-158607935; COSMIC: COSV63750569; COSMIC: COSV63750569;