rs2246434

Variant names:

• chr1-158648665-G-A
• rs2246434
• NM_003126.4:c.3570-12C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-158648665-G-A
• chr1-158648665-G-C

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.3570-12C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.247 in 1,612,600 control chromosomes in the GnomAD database, including 51,402 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4285 hom., cov: 30)
  • Exomes 𝑓: 0.25 (47117 hom.)
• Consequence: SPTA1 NM_003126.4 intron
• Scores: Splicing: ADA: 0.00001248
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.161
• Publications: 18 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 (BayesDel_noAF=-0.82).
• BP6: Variant 1-158648665-G-A is Benign according to our data. Variant chr1-158648665-G-A is described in ClinVar as Benign. ClinVar VariationId is 258930.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.411 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTA1	NM_003126.4	MANE Select	c.3570-12C>T		intron	N/A	NP_003117.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTA1	ENST00000643759.2	MANE Select	c.3570-12C>T		intron	N/A	ENSP00000495214.1

Frequencies

GnomAD3 genomes AF: 0.224 AC: 34069 AN: 151760 Hom.: 4278 Cov.: 30

Gnomad AFR AF: 0.124

Gnomad AMI AF: 0.298

Gnomad AMR AF: 0.283

Gnomad ASJ AF: 0.220

Gnomad EAS AF: 0.426

Gnomad SAS AF: 0.159

Gnomad FIN AF: 0.321

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.246

Gnomad OTH AF: 0.232

GnomAD2 exomes AF: 0.260 AC: 64575 AN: 248566 AF XY: 0.254

Gnomad AFR exome AF: 0.118

Gnomad AMR exome AF: 0.336

Gnomad ASJ exome AF: 0.213

Gnomad EAS exome AF: 0.409

Gnomad FIN exome AF: 0.337

Gnomad NFE exome AF: 0.251

Gnomad OTH exome AF: 0.258

GnomAD4 exome AF: 0.249 AC: 363879 AN: 1460720 Hom.: 47117 Cov.: 39 AF XY: 0.245 AC XY: 178404 AN XY: 726698

African (AFR) AF: 0.115 AC: 3839 AN: 33448

American (AMR) AF: 0.331 AC: 14811 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.212 AC: 5544 AN: 26124

East Asian (EAS) AF: 0.368 AC: 14600 AN: 39662

South Asian (SAS) AF: 0.156 AC: 13426 AN: 86244

European-Finnish (FIN) AF: 0.333 AC: 17683 AN: 53160

Middle Eastern (MID) AF: 0.216 AC: 1203 AN: 5576

European-Non Finnish (NFE) AF: 0.250 AC: 277398 AN: 1111494

Other (OTH) AF: 0.255 AC: 15375 AN: 60330

GnomAD4 genome AF: 0.225 AC: 34107 AN: 151880 Hom.: 4285 Cov.: 30 AF XY: 0.229 AC XY: 17028 AN XY: 74236

African (AFR) AF: 0.125 AC: 5167 AN: 41432

American (AMR) AF: 0.284 AC: 4326 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.220 AC: 761 AN: 3466

East Asian (EAS) AF: 0.426 AC: 2190 AN: 5140

South Asian (SAS) AF: 0.159 AC: 767 AN: 4810

European-Finnish (FIN) AF: 0.321 AC: 3387 AN: 10542

Middle Eastern (MID) AF: 0.224 AC: 66 AN: 294

European-Non Finnish (NFE) AF: 0.246 AC: 16680 AN: 67930

Other (OTH) AF: 0.234 AC: 492 AN: 2106

Alfa AF: 0.237 Hom.: 6135

Bravo AF: 0.222

Asia WGS AF: 0.319 AC: 1108 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Elliptocytosis 2 (1)
-	-	1	Hereditary spherocytosis type 3 (1)
-	-	1	Pyropoikilocytosis, hereditary (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.88
DANN	Benign	0.47
PhyloP100		-0.16
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000012
dbscSNV1_RF	Benign	0.0
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: rs2246434; hg19: chr1-158618455; COSMIC: COSV63755347;