rs2022003

Variant names:

• chr1-158617176-A-T
• rs2022003
• NM_003126.4:c.6600+361T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003126.4(SPTA1):​c.6600+361T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.286 in 151,966 control chromosomes in the GnomAD database, including 6,375 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.29 (6375 hom., cov: 32)
• Consequence: SPTA1 NM_003126.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.149
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.427 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPTA1	NM_003126.4	c.6600+361T>A		intron_variant	Intron 47 of 51	ENST00000643759.2	NP_003117.2
SPTA1	XM_011509916.3	c.6600+361T>A		intron_variant	Intron 48 of 52		XP_011508218.1
SPTA1	XM_011509917.4	c.6582+361T>A		intron_variant	Intron 46 of 50		XP_011508219.1
SPTA1	XM_047428883.1	c.6279+361T>A		intron_variant	Intron 47 of 51		XP_047284839.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPTA1	ENST00000643759.2	c.6600+361T>A		intron_variant	Intron 47 of 51		NM_003126.4	ENSP00000495214.1
SPTA1	ENST00000492934.1	n.115+361T>A		intron_variant	Intron 2 of 2	2
SPTA1	ENST00000498708.1	n.32+361T>A		intron_variant	Intron 1 of 4	3

Frequencies

GnomAD3 genomes AF: 0.286 AC: 43424 AN: 151846 Hom.: 6362 Cov.: 32

Gnomad AFR AF: 0.245

Gnomad AMI AF: 0.326

Gnomad AMR AF: 0.340

Gnomad ASJ AF: 0.302

Gnomad EAS AF: 0.442

Gnomad SAS AF: 0.232

Gnomad FIN AF: 0.339

Gnomad MID AF: 0.358

Gnomad NFE AF: 0.280

Gnomad OTH AF: 0.304

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.286 AC: 43488 AN: 151966 Hom.: 6375 Cov.: 32 AF XY: 0.290 AC XY: 21528 AN XY: 74266

African (AFR) AF: 0.246 AC: 10195 AN: 41440

American (AMR) AF: 0.341 AC: 5196 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.302 AC: 1046 AN: 3468

East Asian (EAS) AF: 0.442 AC: 2284 AN: 5164

South Asian (SAS) AF: 0.233 AC: 1119 AN: 4812

European-Finnish (FIN) AF: 0.339 AC: 3574 AN: 10546

Middle Eastern (MID) AF: 0.357 AC: 105 AN: 294

European-Non Finnish (NFE) AF: 0.280 AC: 19028 AN: 67964

Other (OTH) AF: 0.305 AC: 644 AN: 2110

Alfa AF: 0.280 Hom.: 759

Bravo AF: 0.290

Asia WGS AF: 0.360 AC: 1248 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.1
DANN	Benign	0.63
PhyloP100		-0.15
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2022003; hg19: chr1-158586966;