rs952094

Variant names:

• chr1-158614301-A-G
• rs952094
• NM_003126.4:c.6794T>C

Your query was ambiguous. Multiple possible variants found:

• chr1-158614301-A-G
• chr1-158614301-A-T

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.6794T>C​(p.Ile2265Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.539 in 1,567,036 control chromosomes in the GnomAD database, including 231,666 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (20835 hom., cov: 30)
  • Exomes 𝑓: 0.54 (210831 hom.)
• Consequence: SPTA1 NM_003126.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 2.96
• Publications: 39 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 (MetaRNN=5.061558E-6).
• BP6: Variant 1-158614301-A-G is Benign according to our data. Variant chr1-158614301-A-G is described in ClinVar as Benign. ClinVar VariationId is 258957.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.603 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.6794T>C	p.Ile2265Thr	missense	Exon 49 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.6794T>C	p.Ile2265Thr	missense	Exon 49 of 52	ENSP00000495214.1	P02549-1
	SPTA1	ENST00000481212.5	TSL:3	n.235T>C		non_coding_transcript_exon	Exon 1 of 3
	SPTA1	ENST00000498708.1	TSL:3	n.226T>C		non_coding_transcript_exon	Exon 3 of 5

Frequencies

GnomAD3 genomes AF: 0.520 AC: 78608 AN: 151026 Hom.: 20809 Cov.: 30

Gnomad AFR AF: 0.423

Gnomad AMI AF: 0.553

Gnomad AMR AF: 0.544

Gnomad ASJ AF: 0.570

Gnomad EAS AF: 0.621

Gnomad SAS AF: 0.431

Gnomad FIN AF: 0.633

Gnomad MID AF: 0.611

Gnomad NFE AF: 0.552

Gnomad OTH AF: 0.539

GnomAD2 exomes AF: 0.537 AC: 129167 AN: 240394 AF XY: 0.534

Gnomad AFR exome AF: 0.421

Gnomad AMR exome AF: 0.538

Gnomad ASJ exome AF: 0.576

Gnomad EAS exome AF: 0.606

Gnomad FIN exome AF: 0.635

Gnomad NFE exome AF: 0.551

Gnomad OTH exome AF: 0.544

GnomAD4 exome AF: 0.541 AC: 765443 AN: 1415894 Hom.: 210831 Cov.: 31 AF XY: 0.538 AC XY: 379705 AN XY: 705974

African (AFR) AF: 0.421 AC: 13621 AN: 32316

American (AMR) AF: 0.541 AC: 23141 AN: 42810

Ashkenazi Jewish (ASJ) AF: 0.576 AC: 14715 AN: 25566

East Asian (EAS) AF: 0.598 AC: 23551 AN: 39354

South Asian (SAS) AF: 0.424 AC: 35616 AN: 83938

European-Finnish (FIN) AF: 0.630 AC: 33315 AN: 52876

Middle Eastern (MID) AF: 0.531 AC: 2964 AN: 5584

European-Non Finnish (NFE) AF: 0.546 AC: 586471 AN: 1074734

Other (OTH) AF: 0.546 AC: 32049 AN: 58716

GnomAD4 genome AF: 0.521 AC: 78681 AN: 151142 Hom.: 20835 Cov.: 30 AF XY: 0.526 AC XY: 38759 AN XY: 73716

African (AFR) AF: 0.423 AC: 17443 AN: 41236

American (AMR) AF: 0.544 AC: 8280 AN: 15214

Ashkenazi Jewish (ASJ) AF: 0.570 AC: 1976 AN: 3468

East Asian (EAS) AF: 0.621 AC: 3185 AN: 5128

South Asian (SAS) AF: 0.432 AC: 2076 AN: 4804

European-Finnish (FIN) AF: 0.633 AC: 6506 AN: 10284

Middle Eastern (MID) AF: 0.612 AC: 180 AN: 294

European-Non Finnish (NFE) AF: 0.552 AC: 37386 AN: 67698

Other (OTH) AF: 0.544 AC: 1147 AN: 2108

Alfa AF: 0.542 Hom.: 76470

Bravo AF: 0.515

TwinsUK AF: 0.543 AC: 2013

ALSPAC AF: 0.540 AC: 2083

ESP6500AA AF: 0.430 AC: 1554

ESP6500EA AF: 0.541 AC: 4396

ExAC AF: 0.538 AC: 64923

Asia WGS AF: 0.553 AC: 1914 AN: 3462

EpiCase AF: 0.554

EpiControl AF: 0.550

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
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	15
DANN	Benign	0.12
DEOGEN2	Benign	0.18	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0000051	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.95	N
PhyloP100		3.0
PrimateAI	Benign	0.33	T
REVEL	Benign	0.047
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.057
MPC		0.031
ClinPred		0.0016	T
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.024
gMVP		0.16
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: rs952094; hg19: chr1-158584091; COSMIC: COSV63754417; COSMIC: COSV63754417;