rs2564858

Variant names:

• chr1-158686491-T-C
• rs2564858
• NM_003126.4:c.24+3A>G

Your query was ambiguous. Multiple possible variants found:

• chr1-158686491-T-C
• chr1-158686491-T-A
• chr1-158686491-T-G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_003126.4(SPTA1):​c.24+3A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.995 in 1,589,362 control chromosomes in the GnomAD database, including 787,145 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.97 (72249 hom., cov: 32)
  • Exomes 𝑓: 1.0 (714896 hom.)
• Consequence: SPTA1 NM_003126.4 splice_region, intron
• Scores: Splicing: ADA: 0.001238
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.454
• Publications: 14 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 1-158686491-T-C is Benign according to our data. Variant chr1-158686491-T-C is described in ClinVar as Benign. ClinVar VariationId is 258920.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.24+3A>G		splice_region 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.24+3A>G		splice_region intron	N/A	ENSP00000495214.1	P02549-1

Frequencies

GnomAD3 genomes AF: 0.974 AC: 148060 AN: 152048 Hom.: 72195 Cov.: 32

Gnomad AFR AF: 0.909

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.989

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.999

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.997

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.977

GnomAD2 exomes AF: 0.993 AC: 247474 AN: 249186 AF XY: 0.995

Gnomad AFR exome AF: 0.905

Gnomad AMR exome AF: 0.995

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: 0.997

GnomAD4 exome AF: 0.997 AC: 1433334 AN: 1437196 Hom.: 714896 Cov.: 29 AF XY: 0.998 AC XY: 714922 AN XY: 716616

African (AFR) AF: 0.909 AC: 29728 AN: 32704

American (AMR) AF: 0.994 AC: 44352 AN: 44630

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 25954 AN: 25954

East Asian (EAS) AF: 1.00 AC: 39520 AN: 39520

South Asian (SAS) AF: 1.00 AC: 85592 AN: 85626

European-Finnish (FIN) AF: 1.00 AC: 53360 AN: 53360

Middle Eastern (MID) AF: 0.991 AC: 5536 AN: 5588

European-Non Finnish (NFE) AF: 1.00 AC: 1090217 AN: 1090350

Other (OTH) AF: 0.993 AC: 59075 AN: 59464

GnomAD4 genome AF: 0.974 AC: 148171 AN: 152166 Hom.: 72249 Cov.: 32 AF XY: 0.975 AC XY: 72533 AN XY: 74386

African (AFR) AF: 0.910 AC: 37736 AN: 41490

American (AMR) AF: 0.989 AC: 15095 AN: 15270

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

East Asian (EAS) AF: 1.00 AC: 5190 AN: 5190

South Asian (SAS) AF: 0.999 AC: 4823 AN: 4828

European-Finnish (FIN) AF: 1.00 AC: 10596 AN: 10596

Middle Eastern (MID) AF: 0.993 AC: 292 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 67994 AN: 68006

Other (OTH) AF: 0.978 AC: 2061 AN: 2108

Alfa AF: 0.988 Hom.: 58045

Bravo AF: 0.970

Asia WGS AF: 0.995 AC: 3460 AN: 3476

EpiCase AF: 1.00

EpiControl AF: 1.00

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	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	-0.36
CADD	Benign	14
DANN	Benign	0.82
PhyloP100		0.45
PromoterAI		-0.055	Neutral
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0012
dbscSNV1_RF	Benign	0.050
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: rs2564858; hg19: chr1-158656281;