rs6702040

Variant names:

• chr1-158644408-C-T
• rs6702040
• NM_003126.4:c.4195-12G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-158644408-C-T
• chr1-158644408-C-A
• chr1-158644408-C-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.4195-12G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.301 in 1,612,488 control chromosomes in the GnomAD database, including 75,454 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (9315 hom., cov: 31)
  • Exomes 𝑓: 0.30 (66139 hom.)
• Consequence: SPTA1 NM_003126.4 intron
• Scores: Splicing: ADA: 0.00001060
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -1.63
• Publications: 9 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, PanelApp Australia
• elliptocytosis 2

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

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: PanelApp Australia, 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=-0.91).
• BP6: Variant 1-158644408-C-T is Benign according to our data. Variant chr1-158644408-C-T is described in ClinVar as Benign. ClinVar VariationId is 258935.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.454 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.4195-12G>A		intron	N/A	NP_003117.2	P02549-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTA1	ENST00000643759.2	MANE Select	c.4195-12G>A		intron	N/A	ENSP00000495214.1	P02549-1

Frequencies

GnomAD3 genomes AF: 0.340 AC: 51573 AN: 151708 Hom.: 9304 Cov.: 31

Gnomad AFR AF: 0.459

Gnomad AMI AF: 0.228

Gnomad AMR AF: 0.258

Gnomad ASJ AF: 0.395

Gnomad EAS AF: 0.182

Gnomad SAS AF: 0.292

Gnomad FIN AF: 0.317

Gnomad MID AF: 0.399

Gnomad NFE AF: 0.303

Gnomad OTH AF: 0.332

GnomAD2 exomes AF: 0.292 AC: 72665 AN: 249026 AF XY: 0.294

Gnomad AFR exome AF: 0.461

Gnomad AMR exome AF: 0.198

Gnomad ASJ exome AF: 0.401

Gnomad EAS exome AF: 0.182

Gnomad FIN exome AF: 0.300

Gnomad NFE exome AF: 0.301

Gnomad OTH exome AF: 0.293

GnomAD4 exome AF: 0.297 AC: 433518 AN: 1460664 Hom.: 66139 Cov.: 35 AF XY: 0.298 AC XY: 216408 AN XY: 726680

African (AFR) AF: 0.471 AC: 15738 AN: 33424

American (AMR) AF: 0.205 AC: 9133 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.403 AC: 10520 AN: 26100

East Asian (EAS) AF: 0.200 AC: 7945 AN: 39676

South Asian (SAS) AF: 0.301 AC: 25957 AN: 86240

European-Finnish (FIN) AF: 0.299 AC: 15963 AN: 53390

Middle Eastern (MID) AF: 0.334 AC: 1926 AN: 5762

European-Non Finnish (NFE) AF: 0.295 AC: 328084 AN: 1111074

Other (OTH) AF: 0.302 AC: 18252 AN: 60338

GnomAD4 genome AF: 0.340 AC: 51628 AN: 151824 Hom.: 9315 Cov.: 31 AF XY: 0.339 AC XY: 25171 AN XY: 74178

African (AFR) AF: 0.459 AC: 19002 AN: 41360

American (AMR) AF: 0.258 AC: 3943 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.395 AC: 1366 AN: 3460

East Asian (EAS) AF: 0.183 AC: 943 AN: 5150

South Asian (SAS) AF: 0.292 AC: 1400 AN: 4800

European-Finnish (FIN) AF: 0.317 AC: 3333 AN: 10530

Middle Eastern (MID) AF: 0.405 AC: 119 AN: 294

European-Non Finnish (NFE) AF: 0.303 AC: 20611 AN: 67946

Other (OTH) AF: 0.334 AC: 704 AN: 2108

Alfa AF: 0.295 Hom.: 3937

Bravo AF: 0.339

Asia WGS AF: 0.248 AC: 863 AN: 3478

ClinVar

ClinVar submissions

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
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.47
DANN	Benign	0.55
PhyloP100		-1.6
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000011
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: rs6702040; hg19: chr1-158614198; COSMIC: COSV63760177; COSMIC: COSV63760177;