1-158662741-T-C

Position:

• chr1-158662741-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003126.4(SPTA1):​c.2425A>G​(p.Ile809Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0166 in 1,613,840 control chromosomes in the GnomAD database, including 3,506 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.085 (1830 hom., cov: 32)
  • Exomes 𝑓: 0.0095 (1676 hom.)
• Consequence: SPTA1 NM_003126.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 7.58

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017371178).
• BP6: Variant 1-158662741-T-C is Benign according to our data. Variant chr1-158662741-T-C is described in ClinVar as [Benign]. Clinvar id is 258921.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.288 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPTA1	NM_003126.4	c.2425A>G	p.Ile809Val	missense_variant	17/52	ENST00000643759.2	NP_003117.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPTA1	ENST00000643759.2	c.2425A>G	p.Ile809Val	missense_variant	17/52		NM_003126.4	ENSP00000495214.1

Frequencies

GnomAD3 genomes AF: 0.0849 AC: 12900 AN: 151994 Hom.: 1825 Cov.: 32

Gnomad AFR AF: 0.293

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0342

Gnomad ASJ AF: 0.0173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00121

Gnomad OTH AF: 0.0590

GnomAD3 exomes AF: 0.0227 AC: 5671 AN: 249446 Hom.: 749 AF XY: 0.0177 AC XY: 2395 AN XY: 135330

Gnomad AFR exome AF: 0.303

Gnomad AMR exome AF: 0.0159

Gnomad ASJ exome AF: 0.0168

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000686

Gnomad FIN exome AF: 0.000186

Gnomad NFE exome AF: 0.00147

Gnomad OTH exome AF: 0.0126

GnomAD4 exome AF: 0.00953 AC: 13924 AN: 1461726 Hom.: 1676 Cov.: 31 AF XY: 0.00831 AC XY: 6044 AN XY: 727166

Gnomad4 AFR exome AF: 0.305

Gnomad4 AMR exome AF: 0.0182

Gnomad4 ASJ exome AF: 0.0161

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00101

Gnomad4 FIN exome AF: 0.000187

Gnomad4 NFE exome AF: 0.000769

Gnomad4 OTH exome AF: 0.0219

GnomAD4 genome AF: 0.0850 AC: 12924 AN: 152114 Hom.: 1830 Cov.: 32 AF XY: 0.0828 AC XY: 6162 AN XY: 74388

Gnomad4 AFR AF: 0.293

Gnomad4 AMR AF: 0.0341

Gnomad4 ASJ AF: 0.0173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00121

Gnomad4 OTH AF: 0.0583

Alfa AF: 0.0317 Hom.: 380

Bravo AF: 0.0961

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.278 AC: 1083

ESP6500EA AF: 0.00230 AC: 19

ExAC AF: 0.0273 AC: 3297

Asia WGS AF: 0.0200 AC: 70 AN: 3478

EpiCase AF: 0.00147

EpiControl AF: 0.00267

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Elliptocytosis 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Hereditary spherocytosis type 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Pyropoikilocytosis, hereditary Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.25	T;T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	.;D
MetaRNN	Benign	0.0017	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.8	L;L
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.91	N;.
REVEL	Benign	0.23
Sift	Pathogenic	0.0	D;.
Sift4G	Uncertain	0.023	D;.
Polyphen		1.0	D;D
Vest4		0.35
MPC		0.21
ClinPred		0.036	T
GERP RS		4.3
Varity_R		0.41
gMVP		0.10

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

Publications

LitVar

Other links and lift over

dbSNP: rs7547313; hg19: chr1-158632531; COSMIC: COSV63753952; COSMIC: COSV63753952;