1-158642929-C-G

Variant names:

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

Variant summary

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

The NM_003126.4(SPTA1):​c.4490G>C​(p.Gly1497Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,540 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• 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, 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: Uncertain_significance. The variant received 2 ACMG points.

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

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.4490G>C	p.Gly1497Ala	missense	Exon 32 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.4490G>C	p.Gly1497Ala	missense	Exon 32 of 52	ENSP00000495214.1	P02549-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461540 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727070

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.00 AC: 0 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111810

Other (OTH) AF: 0.00 AC: 0 AN: 60372

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	17
DANN	Benign	0.89
DEOGEN2	Uncertain	0.46	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.40
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.52	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		4.8
PrimateAI	Benign	0.42	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Benign	0.11
Sift	Uncertain	0.029	D
Sift4G	Uncertain	0.045	D
Polyphen		0.94	P
Vest4		0.50
MutPred		0.28		Gain of ubiquitination at K1495 (P = 0.1204)
MVP		0.63
MPC		0.18
ClinPred		0.56	D
GERP RS		0.0036
Varity_R		0.27
gMVP		0.083
Mutation Taster		=83/17	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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;