rs2482965

Variant names:

• chr1-158649938-A-C
• rs2482965
• NM_003126.4:c.3487T>G

Your query was ambiguous. Multiple possible variants found:

• chr1-158649938-A-C
• chr1-158649938-A-G
• chr1-158649938-A-T

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.3487T>G​(p.Ser1163Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.999 in 1,613,086 control chromosomes in the GnomAD database, including 804,898 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1163F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.99 (75305 hom., cov: 35)
  • Exomes 𝑓: 1.0 (729593 hom.)
• Consequence: SPTA1 NM_003126.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.317
• Publications: 33 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=1.4069386E-6).
• BP6: Variant 1-158649938-A-C is Benign according to our data. Variant chr1-158649938-A-C is described in ClinVar as Benign. ClinVar VariationId is 258929.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003126.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTA1	NM_003126.4	MANE Select	c.3487T>G	p.Ser1163Ala	missense	Exon 25 of 52	NP_003117.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTA1	ENST00000643759.2	MANE Select	c.3487T>G	p.Ser1163Ala	missense	Exon 25 of 52	ENSP00000495214.1

Frequencies

GnomAD3 genomes AF: 0.994 AC: 151359 AN: 152244 Hom.: 75246 Cov.: 35

Gnomad AFR AF: 0.980

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.998

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.997

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.999

GnomAD2 exomes AF: 0.998 AC: 247313 AN: 247692 AF XY: 0.999

Gnomad AFR exome AF: 0.978

Gnomad AMR exome AF: 0.999

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 1.00

GnomAD4 exome AF: 0.999 AC: 1459949 AN: 1460724 Hom.: 729593 Cov.: 40 AF XY: 1.00 AC XY: 726218 AN XY: 726538

African (AFR) AF: 0.981 AC: 32809 AN: 33452

American (AMR) AF: 0.999 AC: 44543 AN: 44594

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 26098 AN: 26098

East Asian (EAS) AF: 1.00 AC: 39674 AN: 39674

South Asian (SAS) AF: 1.00 AC: 86040 AN: 86044

European-Finnish (FIN) AF: 1.00 AC: 53318 AN: 53318

Middle Eastern (MID) AF: 0.999 AC: 5763 AN: 5766

European-Non Finnish (NFE) AF: 1.00 AC: 1111426 AN: 1111432

Other (OTH) AF: 0.999 AC: 60278 AN: 60346

GnomAD4 genome AF: 0.994 AC: 151477 AN: 152362 Hom.: 75305 Cov.: 35 AF XY: 0.995 AC XY: 74089 AN XY: 74498

African (AFR) AF: 0.980 AC: 40743 AN: 41588

American (AMR) AF: 0.998 AC: 15271 AN: 15306

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5176 AN: 5176

South Asian (SAS) AF: 1.00 AC: 4830 AN: 4830

European-Finnish (FIN) AF: 1.00 AC: 10624 AN: 10624

Middle Eastern (MID) AF: 0.997 AC: 293 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 68043 AN: 68044

Other (OTH) AF: 0.999 AC: 2113 AN: 2116

Alfa AF: 0.998 Hom.: 175214

Bravo AF: 0.993

TwinsUK AF: 1.00 AC: 3708

ALSPAC AF: 1.00 AC: 3854

ESP6500AA AF: 0.981 AC: 3642

ESP6500EA AF: 1.00 AC: 8218

ExAC AF: 0.998 AC: 120486

Asia WGS AF: 0.999 AC: 3476 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	2	Elliptocytosis 2 (2)
-	-	2	Hereditary spherocytosis type 3 (2)
-	-	2	Pyropoikilocytosis, hereditary (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	7.4
DANN	Benign	0.95
DEOGEN2	Benign	0.19	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.098	N
LIST_S2	Benign	0.035	T
MetaRNN	Benign	0.0000014	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.69	N
PhyloP100		0.32
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.069
Sift	Benign	0.49	T
Sift4G	Benign	0.51	T
Polyphen		0.0	B
Vest4		0.019
MPC		0.025
ClinPred		0.0080	T
GERP RS		-1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.064
gMVP		0.085
Mutation Taster		=98/2	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: rs2482965; hg19: chr1-158619728; COSMIC: COSV107461993;