rs16830483

Variant names:

• chr1-158634601-T-C
• rs16830483
• NM_003126.4:c.5507A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003126.4(SPTA1):​c.5507A>G​(p.Asn1836Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0236 in 1,614,126 control chromosomes in the GnomAD database, including 1,302 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.053 (484 hom., cov: 32)
  • Exomes 𝑓: 0.020 (818 hom.)
• Consequence: SPTA1 NM_003126.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.26
• Publications: 10 publications found

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 Gene-Disease associations (from GenCC):

• hereditary spherocytosis type 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Ambry Genetics
• elliptocytosis 2

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine
• pyropoikilocytosis, hereditary

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• hereditary elliptocytosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary spherocytosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015079081).
• BP6: Variant 1-158634601-T-C is Benign according to our data. Variant chr1-158634601-T-C is described in ClinVar as [Benign]. Clinvar id is 258947.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
SPTA1	NM_003126.4	c.5507A>G	p.Asn1836Ser	missense_variant	Exon 39 of 52	ENST00000643759.2	NP_003117.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPTA1	ENST00000643759.2	c.5507A>G	p.Asn1836Ser	missense_variant	Exon 39 of 52		NM_003126.4	ENSP00000495214.1
SPTA1	ENST00000461624.1	n.53A>G		non_coding_transcript_exon_variant	Exon 1 of 5	2

Frequencies

GnomAD3 genomes AF: 0.0530 AC: 8063 AN: 152154 Hom.: 482 Cov.: 32

Gnomad AFR AF: 0.145

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0268

Gnomad ASJ AF: 0.0496

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0459

Gnomad FIN AF: 0.00885

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0153

Gnomad OTH AF: 0.0483

GnomAD2 exomes AF: 0.0291 AC: 7267 AN: 249390 AF XY: 0.0291

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 FIN exome AF: 0.00812

Gnomad NFE exome AF: 0.0171

Gnomad OTH exome AF: 0.0297

GnomAD4 exome AF: 0.0205 AC: 29927 AN: 1461854 Hom.: 818 Cov.: 32 AF XY: 0.0213 AC XY: 15462 AN XY: 727222

African (AFR) AF: 0.146 AC: 4904 AN: 33476

American (AMR) AF: 0.0209 AC: 933 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0529 AC: 1382 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39694

South Asian (SAS) AF: 0.0539 AC: 4647 AN: 86258

European-Finnish (FIN) AF: 0.00929 AC: 496 AN: 53402

Middle Eastern (MID) AF: 0.0855 AC: 493 AN: 5768

European-Non Finnish (NFE) AF: 0.0138 AC: 15300 AN: 1112008

Other (OTH) AF: 0.0293 AC: 1770 AN: 60396

GnomAD4 genome AF: 0.0532 AC: 8095 AN: 152272 Hom.: 484 Cov.: 32 AF XY: 0.0525 AC XY: 3910 AN XY: 74454

African (AFR) AF: 0.145 AC: 6034 AN: 41516

American (AMR) AF: 0.0267 AC: 409 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0496 AC: 172 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.0457 AC: 220 AN: 4816

European-Finnish (FIN) AF: 0.00885 AC: 94 AN: 10624

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0153 AC: 1041 AN: 68036

Other (OTH) AF: 0.0478 AC: 101 AN: 2114

Alfa AF: 0.0305 Hom.: 724

Bravo AF: 0.0583

TwinsUK AF: 0.0135 AC: 50

ALSPAC AF: 0.0143 AC: 55

ESP6500AA AF: 0.139 AC: 544

ESP6500EA AF: 0.0151 AC: 125

ExAC AF: 0.0316 AC: 3825

Asia WGS AF: 0.0290 AC: 100 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Oct 24, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Elliptocytosis 2 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary spherocytosis type 3 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	0.053
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	11
DANN	Benign	0.89
DEOGEN2	Benign	0.29	T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.20	N
LIST_S2	Uncertain	0.90	.;D
MetaRNN	Benign	0.0015	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.18	N;N
PhyloP100		1.3
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.7	N;.
REVEL	Benign	0.074
Sift	Benign	0.68	T;.
Sift4G	Benign	0.78	T;.
Polyphen		0.0020	B;B
Vest4		0.037
MPC		0.025
ClinPred		0.010	T
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.047
gMVP		0.031
Mutation Taster		=89/11	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs16830483; hg19: chr1-158604391; COSMIC: COSV63756982; COSMIC: COSV63756982;