rs703121

Variant names:

• chr1-158677732-A-C
• rs703121
• NM_003126.4:c.915T>G

Your query was ambiguous. Multiple possible variants found:

• chr1-158677732-A-C
• chr1-158677732-A-G
• chr1-158677732-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003126.4(SPTA1):​c.915T>G​(p.Ser305Arg) 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. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S305S) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SPTA1 NM_003126.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.01
• Publications: 21 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20885497).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPTA1	NM_003126.4	c.915T>G	p.Ser305Arg	missense_variant	Exon 7 of 52	ENST00000643759.2	NP_003117.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPTA1	ENST00000643759.2	c.915T>G	p.Ser305Arg	missense_variant	Exon 7 of 52		NM_003126.4	ENSP00000495214.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 60

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T;T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.55	.;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.60	N;N
PhyloP100		1.0
PrimateAI	Benign	0.36	T
PROVEAN	Benign	1.2	N;.
REVEL	Benign	0.11
Sift	Uncertain	0.0030	D;.
Sift4G	Benign	0.15	T;.
Polyphen		0.012	B;B
Vest4		0.38
MutPred		0.62		Gain of ubiquitination at K307 (P = 0.0499);Gain of ubiquitination at K307 (P = 0.0499);
MVP		0.64
MPC		0.098
ClinPred		0.65	D
GERP RS		2.3
Varity_R		0.29
gMVP		0.11
Mutation Taster		=81/19	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: rs703121; hg19: chr1-158647522;