rs41273523

Variant names:

• chr1-158642929-C-A
• rs41273523
• NM_003126.4:c.4490G>T

Your query was ambiguous. Multiple possible variants found:

• chr1-158642929-C-A
• chr1-158642929-C-G
• chr1-158642929-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003126.4(SPTA1):​c.4490G>T​(p.Gly1497Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. G1497E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPTA1 NM_003126.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.75
• Publications: 0 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
• 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPTA1	NM_003126.4	c.4490G>T	p.Gly1497Val	missense_variant	Exon 32 of 52	ENST00000643759.2	NP_003117.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPTA1	ENST00000643759.2	c.4490G>T	p.Gly1497Val	missense_variant	Exon 32 of 52		NM_003126.4	ENSP00000495214.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.083	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.50	D;D
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.31
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.76	.;T
M_CAP	Benign	0.049	D
MetaRNN	Uncertain	0.70	D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M;M
PhyloP100		4.8
PrimateAI	Benign	0.42	T
PROVEAN	Pathogenic	-6.9	D;.
REVEL	Benign	0.20
Sift	Uncertain	0.0020	D;.
Sift4G	Uncertain	0.0070	D;.
Polyphen		0.99	D;D
Vest4		0.60
MutPred		0.39		Loss of ubiquitination at K1495 (P = 0.1166);Loss of ubiquitination at K1495 (P = 0.1166);
MVP		0.71
MPC		0.23
ClinPred		0.94	D
GERP RS		0.0036
Varity_R		0.41
gMVP		0.14
Mutation Taster		=86/14	polymorphism

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: rs41273523; hg19: chr1-158612719;