rs16840450

Positions:

• chr1-158657525-T-A
• chr1-158657525-T-C
• chr1-158657525-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003126.4(SPTA1):​c.2757A>T​(p.Glu919Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPTA1 NM_003126.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0820

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPTA1	NM_003126.4	c.2757A>T	p.Glu919Asp	missense_variant	19/52	ENST00000643759.2	NP_003117.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPTA1	ENST00000643759.2	c.2757A>T	p.Glu919Asp	missense_variant	19/52		NM_003126.4	ENSP00000495214	P1
SPTA1	ENST00000647256.1	n.357A>T		non_coding_transcript_exon_variant	2/3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	15
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T;T
Eigen	Benign	-0.090
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.62	D
LIST_S2	Uncertain	0.94	.;D
M_CAP	Benign	0.022	T
MetaRNN	Uncertain	0.63	D;D
MetaSVM	Benign	-0.62	T
MutationAssessor	Uncertain	2.5	M;M
MutationTaster	Benign	0.017	P;P
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.4	N;.
REVEL	Benign	0.29
Sift	Benign	0.059	T;.
Sift4G	Uncertain	0.0070	D;.
Polyphen		0.93	P;P
Vest4		0.45
MutPred		0.41		Gain of ubiquitination at K918 (P = 0.1278);Gain of ubiquitination at K918 (P = 0.1278);
MVP		0.76
MPC		0.18
ClinPred		0.97	D
GERP RS		-3.5
Varity_R		0.26
gMVP		0.33

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

LitVar

Other links and lift over

dbSNP: rs16840450; hg19: chr1-158627315;