Genetic Variant SPTA1:p.Ile2265Asn (chr1-158614301-A-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003126.4(SPTA1):c.6794T>A(p.Ile2265Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I2265T) has been classified as Benign.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SPTA1
NM_003126.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.96

Publications

39 publications found

Variant links:

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
elliptocytosis 2
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine
pyropoikilocytosis, hereditary
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
hereditary elliptocytosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hereditary spherocytosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

SPTA1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0779095).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPTA1	NM_003126.4 link	c.6794T>A	p.Ile2265Asn	missense_variant	Exon 49 of 52	ENST00000643759.2	NP_003117.2	P02549-1
SPTA1	XM_011509916.3 link	c.6794T>A	p.Ile2265Asn	missense_variant	Exon 50 of 53		XP_011508218.1	P02549-1
SPTA1	XM_011509917.4 link	c.6776T>A	p.Ile2259Asn	missense_variant	Exon 48 of 51		XP_011508219.1
SPTA1	XM_047428883.1 link	c.6473T>A	p.Ile2158Asn	missense_variant	Exon 49 of 52		XP_047284839.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SPTA1	ENST00000643759.2 link	c.6794T>A	p.Ile2265Asn	missense_variant	Exon 49 of 52		NM_003126.4	ENSP00000495214.1	P02549-1
SPTA1	ENST00000481212.5 link	n.235T>A		non_coding_transcript_exon_variant	Exon 1 of 3	3
SPTA1	ENST00000498708.1 link	n.226T>A		non_coding_transcript_exon_variant	Exon 3 of 5	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1429264

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

712372

African (AFR)

AF:

0.00

AC:

AN:

32642

American (AMR)

AF:

0.00

AC:

AN:

43364

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25728

East Asian (EAS)

AF:

0.00

AC:

AN:

39488

South Asian (SAS)

AF:

0.00

AC:

AN:

84520

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53070

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5636

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1085566

Other (OTH)

AF:

0.00

AC:

AN:

59250

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

76470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.18

T;T

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.73

FATHMM_MKL

Uncertain

0.80

LIST_S2

Pathogenic

0.99

.;D

M_CAP

Benign

0.027

MetaRNN

Benign

0.078

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

N;N

PhyloP100

3.0

PrimateAI

Benign

0.35

REVEL

Benign

0.055

Sift4G

Uncertain

0.040

D;.

Polyphen

0.0

B;B

Vest4

0.26

MutPred

0.45

Gain of disorder (P = 0.0251);Gain of disorder (P = 0.0251);

MVP

0.48

MPC

0.039

ClinPred

0.083

GERP RS

1.3

Varity_R

0.065

gMVP

0.25

Mutation Taster

=100/0

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over