1-158614301-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_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. 14/19 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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.96

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 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/exons	MANE	UniProt
SPTA1	NM_003126.4	c.6794T>A	p.Ile2265Asn	missense_variant	49/52	ENST00000643759.2
SPTA1	XM_011509916.3	c.6794T>A	p.Ile2265Asn	missense_variant	50/53
SPTA1	XM_011509917.4	c.6776T>A	p.Ile2259Asn	missense_variant	48/51
SPTA1	XM_047428883.1	c.6473T>A	p.Ile2158Asn	missense_variant	49/52

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPTA1	ENST00000643759.2	c.6794T>A	p.Ile2265Asn	missense_variant	49/52		NM_003126.4	P1
SPTA1	ENST00000481212.5	n.235T>A		non_coding_transcript_exon_variant	1/3	3
SPTA1	ENST00000498708.1	n.226T>A		non_coding_transcript_exon_variant	3/5	3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1429264 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 712372

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

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	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	21
Dann	Benign	0.90
DEOGEN2	Benign	0.18	T;T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.73
FATHMM_MKL	Uncertain	0.80	D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.078	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N;N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.35	T
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	T
GERP RS		1.3
Varity_R		0.065
gMVP		0.25

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: rs952094; hg19: chr1-158584091;