rs857716

Variant names:

• chr1-158617600-C-T
• rs857716
• NM_003126.4:c.6549-12G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-158617600-C-T
• chr1-158617600-C-A
• chr1-158617600-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.6549-12G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.539 in 1,603,432 control chromosomes in the GnomAD database, including 236,032 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (20422 hom., cov: 32)
  • Exomes 𝑓: 0.54 (215610 hom.)
• Consequence: SPTA1 NM_003126.4 intron
• Scores: Splicing: ADA: 0.0009544
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:14
• Conservation: PhyloP100: -1.69
• Publications: 10 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=-0.69).
• BP6: Variant 1-158617600-C-T is Benign according to our data. Variant chr1-158617600-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 258955.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.606 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.6549-12G>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.6549-12G>A		intron	N/A	ENSP00000495214.1	P02549-1
	SPTA1	ENST00000492934.1	TSL:2	n.64-12G>A		intron	N/A
	SPTA1	ENST00000498708.1	TSL:3	n.-32G>A		upstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.510 AC: 77478 AN: 151854 Hom.: 20402 Cov.: 32

Gnomad AFR AF: 0.382

Gnomad AMI AF: 0.555

Gnomad AMR AF: 0.543

Gnomad ASJ AF: 0.578

Gnomad EAS AF: 0.624

Gnomad SAS AF: 0.431

Gnomad FIN AF: 0.640

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.553

Gnomad OTH AF: 0.533

GnomAD2 exomes AF: 0.538 AC: 133404 AN: 248152 AF XY: 0.535

Gnomad AFR exome AF: 0.381

Gnomad AMR exome AF: 0.540

Gnomad ASJ exome AF: 0.585

Gnomad EAS exome AF: 0.608

Gnomad FIN exome AF: 0.634

Gnomad NFE exome AF: 0.553

Gnomad OTH exome AF: 0.547

GnomAD4 exome AF: 0.542 AC: 786672 AN: 1451460 Hom.: 215610 Cov.: 32 AF XY: 0.539 AC XY: 389653 AN XY: 722610

African (AFR) AF: 0.383 AC: 12747 AN: 33312

American (AMR) AF: 0.541 AC: 24163 AN: 44638

Ashkenazi Jewish (ASJ) AF: 0.583 AC: 15190 AN: 26042

East Asian (EAS) AF: 0.606 AC: 24024 AN: 39630

South Asian (SAS) AF: 0.428 AC: 36852 AN: 86040

European-Finnish (FIN) AF: 0.630 AC: 33609 AN: 53342

Middle Eastern (MID) AF: 0.527 AC: 3031 AN: 5750

European-Non Finnish (NFE) AF: 0.548 AC: 604392 AN: 1102710

Other (OTH) AF: 0.544 AC: 32664 AN: 59996

GnomAD4 genome AF: 0.510 AC: 77549 AN: 151972 Hom.: 20422 Cov.: 32 AF XY: 0.516 AC XY: 38327 AN XY: 74266

African (AFR) AF: 0.382 AC: 15846 AN: 41464

American (AMR) AF: 0.543 AC: 8284 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.578 AC: 2006 AN: 3468

East Asian (EAS) AF: 0.624 AC: 3221 AN: 5162

South Asian (SAS) AF: 0.432 AC: 2080 AN: 4818

European-Finnish (FIN) AF: 0.640 AC: 6742 AN: 10540

Middle Eastern (MID) AF: 0.602 AC: 177 AN: 294

European-Non Finnish (NFE) AF: 0.553 AC: 37552 AN: 67950

Other (OTH) AF: 0.537 AC: 1135 AN: 2112

Alfa AF: 0.473 Hom.: 3962

Bravo AF: 0.501

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	Hereditary spherocytosis type 3 (3)
-	-	3	not specified (3)
-	-	2	Elliptocytosis 2 (2)
-	-	2	Pyropoikilocytosis, hereditary (2)
1	-	-	Hemolytic anemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	3.8
DANN	Benign	0.65
PhyloP100		-1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00095
dbscSNV1_RF	Benign	0.10
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: rs857716; hg19: chr1-158587390; COSMIC: COSV107462148; COSMIC: COSV107462148;