chr1-158618068-G-A

Variant names:

• chr1-158618068-G-A
• rs28525570
• NM_003126.4:c.6531-12C>T

Variant summary

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

The ENST00000643759.2(SPTA1):​c.6531-12C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.27 in 1,602,240 control chromosomes in the GnomAD database, including 60,252 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.25 (5121 hom., cov: 32)
  • Exomes 𝑓: 0.27 (55131 hom.)
• Consequence: SPTA1 ENST00000643759.2 intron
• Scores: Splicing: ADA: 0.0004991
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2 B:7
• Conservation: PhyloP100: 0.574
• Publications: 28 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=-0.54).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.285 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000643759.2. 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.6531-12C>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.6531-12C>T		intron	N/A	ENSP00000495214.1
	SPTA1	ENST00000492934.1	TSL:2	n.34C>T		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes AF: 0.254 AC: 38595 AN: 151962 Hom.: 5120 Cov.: 32

Gnomad AFR AF: 0.199

Gnomad AMI AF: 0.229

Gnomad AMR AF: 0.219

Gnomad ASJ AF: 0.342

Gnomad EAS AF: 0.185

Gnomad SAS AF: 0.245

Gnomad FIN AF: 0.309

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.288

Gnomad OTH AF: 0.261

GnomAD2 exomes AF: 0.254 AC: 63402 AN: 249186 AF XY: 0.259

Gnomad AFR exome AF: 0.198

Gnomad AMR exome AF: 0.171

Gnomad ASJ exome AF: 0.349

Gnomad EAS exome AF: 0.185

Gnomad FIN exome AF: 0.292

Gnomad NFE exome AF: 0.284

Gnomad OTH exome AF: 0.259

GnomAD4 exome AF: 0.271 AC: 393274 AN: 1450160 Hom.: 55131 Cov.: 32 AF XY: 0.272 AC XY: 196331 AN XY: 721926

African (AFR) AF: 0.197 AC: 6561 AN: 33310

American (AMR) AF: 0.176 AC: 7861 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.349 AC: 9088 AN: 26028

East Asian (EAS) AF: 0.203 AC: 8029 AN: 39644

South Asian (SAS) AF: 0.245 AC: 21094 AN: 86010

European-Finnish (FIN) AF: 0.289 AC: 15453 AN: 53382

Middle Eastern (MID) AF: 0.242 AC: 1391 AN: 5750

European-Non Finnish (NFE) AF: 0.280 AC: 308011 AN: 1101380

Other (OTH) AF: 0.263 AC: 15786 AN: 59980

GnomAD4 genome AF: 0.254 AC: 38604 AN: 152080 Hom.: 5121 Cov.: 32 AF XY: 0.255 AC XY: 18981 AN XY: 74334

African (AFR) AF: 0.198 AC: 8227 AN: 41490

American (AMR) AF: 0.218 AC: 3337 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.342 AC: 1185 AN: 3468

East Asian (EAS) AF: 0.185 AC: 957 AN: 5160

South Asian (SAS) AF: 0.245 AC: 1182 AN: 4830

European-Finnish (FIN) AF: 0.309 AC: 3263 AN: 10558

Middle Eastern (MID) AF: 0.327 AC: 96 AN: 294

European-Non Finnish (NFE) AF: 0.288 AC: 19592 AN: 67984

Other (OTH) AF: 0.264 AC: 557 AN: 2110

Alfa AF: 0.214 Hom.: 769

Bravo AF: 0.242

Asia WGS AF: 0.209 AC: 729 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	15
DANN	Benign	0.80
PhyloP100		0.57
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=99/1	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00050
dbscSNV1_RF	Benign	0.26
SpliceAI score (max)		0.030		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: rs28525570; hg19: chr1-158587858; COSMIC: COSV63760163; COSMIC: COSV63760163;