rs202243588

Positions:

• chr1-158669553-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6 BS2_Supporting

The NM_003126.4(SPTA1):​c.1688G>A​(p.Arg563Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000759 in 1,614,086 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00050 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00079 (16 hom.)
• Consequence: SPTA1 NM_003126.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:3
• Conservation: PhyloP100: 5.85

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013475835).
• BP6: Variant 1-158669553-C-T is Benign according to our data. Variant chr1-158669553-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 544820.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=4, Likely_benign=2}.
• BS2: High Homozygotes in GnomAdExome4 at 16 AD,AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPTA1	NM_003126.4	c.1688G>A	p.Arg563Gln	missense_variant	14/52	ENST00000643759.2	NP_003117.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPTA1	ENST00000643759.2	c.1688G>A	p.Arg563Gln	missense_variant	14/52		NM_003126.4	ENSP00000495214	P1

Frequencies

GnomAD3 genomes AF: 0.000493 AC: 75 AN: 152158 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00559

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000514

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00113 AC: 283 AN: 249420 Hom.: 5 AF XY: 0.00146 AC XY: 198 AN XY: 135296

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.000551

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00640

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000477

Gnomad OTH exome AF: 0.00132

GnomAD4 exome AF: 0.000786 AC: 1149 AN: 1461810 Hom.: 16 Cov.: 33 AF XY: 0.000997 AC XY: 725 AN XY: 727216

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.000626

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00715

Gnomad4 FIN exome AF: 0.000262

Gnomad4 NFE exome AF: 0.000397

Gnomad4 OTH exome AF: 0.000613

GnomAD4 genome AF: 0.000499 AC: 76 AN: 152276 Hom.: 0 Cov.: 32 AF XY: 0.000618 AC XY: 46 AN XY: 74448

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00580

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000515

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000719 Hom.: 0

Bravo AF: 0.000340

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000255 AC: 1

ESP6500EA AF: 0.000481 AC: 4

ExAC AF: 0.00115 AC: 139

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 11, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	SPTA1: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 07, 2023	- -

Hereditary spherocytosis type 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Familial hemolytic anemia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Department of Genetic, Henri Mondor Hospital, Assistance Publique des Hôpitaux de Paris

Feb 27, 2018

- -

Pyropoikilocytosis, hereditary Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Elliptocytosis 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	23
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.50	D;D
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.97	.;D
M_CAP	Uncertain	0.085	D
MetaRNN	Benign	0.013	T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Pathogenic	3.1	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-3.5	D;.
REVEL	Uncertain	0.30
Sift	Uncertain	0.0040	D;.
Sift4G	Uncertain	0.011	D;.
Polyphen		1.0	D;D
Vest4		0.70
MVP		0.82
MPC		0.21
ClinPred		0.11	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.27
gMVP		0.48

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: rs202243588; hg19: chr1-158639343;