rs2251969

Variant names:

• chr1-158612856-T-C
• rs2251969
• NM_003126.4:c.7095A>G

Your query was ambiguous. Multiple possible variants found:

• chr1-158612856-T-C
• chr1-158612856-T-A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003126.4(SPTA1):​c.7095A>G​(p.Ala2365Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.542 in 1,613,310 control chromosomes in the GnomAD database, including 238,993 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (21074 hom., cov: 31)
  • Exomes 𝑓: 0.54 (217919 hom.)
• Consequence: SPTA1 NM_003126.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -1.73
• Publications: 17 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 1-158612856-T-C is Benign according to our data. Variant chr1-158612856-T-C is described in ClinVar as Benign. ClinVar VariationId is 258958.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.73 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.605 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.7095A>G	p.Ala2365Ala	synonymous	Exon 51 of 52	NP_003117.2	P02549-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTA1	ENST00000643759.2	MANE Select	c.7095A>G	p.Ala2365Ala	synonymous	Exon 51 of 52	ENSP00000495214.1	P02549-1
	SPTA1	ENST00000481212.5	TSL:3	n.536A>G		non_coding_transcript_exon	Exon 3 of 3
	SPTA1	ENST00000498708.1	TSL:3	n.527A>G		non_coding_transcript_exon	Exon 5 of 5

Frequencies

GnomAD3 genomes AF: 0.521 AC: 79168 AN: 151856 Hom.: 21048 Cov.: 31

Gnomad AFR AF: 0.423

Gnomad AMI AF: 0.555

Gnomad AMR AF: 0.544

Gnomad ASJ AF: 0.570

Gnomad EAS AF: 0.623

Gnomad SAS AF: 0.432

Gnomad FIN AF: 0.638

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.553

Gnomad OTH AF: 0.537

GnomAD2 exomes AF: 0.542 AC: 134682 AN: 248610 AF XY: 0.539

Gnomad AFR exome AF: 0.423

Gnomad AMR exome AF: 0.544

Gnomad ASJ exome AF: 0.580

Gnomad EAS exome AF: 0.611

Gnomad FIN exome AF: 0.635

Gnomad NFE exome AF: 0.555

Gnomad OTH exome AF: 0.550

GnomAD4 exome AF: 0.544 AC: 795007 AN: 1461336 Hom.: 217919 Cov.: 48 AF XY: 0.541 AC XY: 393337 AN XY: 726994

African (AFR) AF: 0.427 AC: 14297 AN: 33458

American (AMR) AF: 0.545 AC: 24344 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.578 AC: 15092 AN: 26126

East Asian (EAS) AF: 0.599 AC: 23766 AN: 39694

South Asian (SAS) AF: 0.430 AC: 37059 AN: 86244

European-Finnish (FIN) AF: 0.630 AC: 33649 AN: 53398

Middle Eastern (MID) AF: 0.530 AC: 3054 AN: 5766

European-Non Finnish (NFE) AF: 0.549 AC: 610648 AN: 1111600

Other (OTH) AF: 0.548 AC: 33098 AN: 60368

GnomAD4 genome AF: 0.521 AC: 79243 AN: 151974 Hom.: 21074 Cov.: 31 AF XY: 0.527 AC XY: 39156 AN XY: 74272

African (AFR) AF: 0.423 AC: 17538 AN: 41468

American (AMR) AF: 0.544 AC: 8302 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.570 AC: 1976 AN: 3466

East Asian (EAS) AF: 0.623 AC: 3202 AN: 5138

South Asian (SAS) AF: 0.433 AC: 2084 AN: 4816

European-Finnish (FIN) AF: 0.638 AC: 6739 AN: 10558

Middle Eastern (MID) AF: 0.606 AC: 177 AN: 292

European-Non Finnish (NFE) AF: 0.553 AC: 37575 AN: 67950

Other (OTH) AF: 0.542 AC: 1144 AN: 2110

Alfa AF: 0.540 Hom.: 10008

Bravo AF: 0.515

Asia WGS AF: 0.559 AC: 1941 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	-0.73
CADD	Benign	4.3
DANN	Benign	0.58
PhyloP100		-1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs2251969; hg19: chr1-158582646; COSMIC: COSV63755039; COSMIC: COSV63755039;