rs78394850

Positions:

• chr1-158623057-G-A
• chr1-158623057-G-T

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.6046C>T​(p.Arg2016Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0241 in 1,613,990 control chromosomes in the GnomAD database, including 1,324 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.054 (487 hom., cov: 33)
  • Exomes 𝑓: 0.021 (837 hom.)
• Consequence: SPTA1 NM_003126.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 9.54

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038462281).
• BP6: Variant 1-158623057-G-A is Benign according to our data. Variant chr1-158623057-G-A is described in ClinVar as [Benign]. Clinvar id is 258951.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-158623057-G-A is described in Lovd as [Benign]. Variant chr1-158623057-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.143 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPTA1	NM_003126.4	c.6046C>T	p.Arg2016Cys	missense_variant	43/52	ENST00000643759.2	NP_003117.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPTA1	ENST00000643759.2	c.6046C>T	p.Arg2016Cys	missense_variant	43/52		NM_003126.4	ENSP00000495214	P1
SPTA1	ENST00000461624.1	n.592C>T		non_coding_transcript_exon_variant	5/5	2

Frequencies

GnomAD3 genomes AF: 0.0534 AC: 8125 AN: 152048 Hom.: 485 Cov.: 33

Gnomad AFR AF: 0.145

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0271

Gnomad ASJ AF: 0.0496

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0460

Gnomad FIN AF: 0.00952

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0159

Gnomad OTH AF: 0.0483

GnomAD3 exomes AF: 0.0295 AC: 7359 AN: 249486 Hom.: 277 AF XY: 0.0294 AC XY: 3980 AN XY: 135344

Gnomad AFR exome AF: 0.144

Gnomad AMR exome AF: 0.0200

Gnomad ASJ exome AF: 0.0517

Gnomad EAS exome AF: 0.000278

Gnomad SAS exome AF: 0.0502

Gnomad FIN exome AF: 0.00840

Gnomad NFE exome AF: 0.0178

Gnomad OTH exome AF: 0.0301

GnomAD4 exome AF: 0.0211 AC: 30772 AN: 1461824 Hom.: 837 Cov.: 30 AF XY: 0.0218 AC XY: 15833 AN XY: 727204

Gnomad4 AFR exome AF: 0.147

Gnomad4 AMR exome AF: 0.0210

Gnomad4 ASJ exome AF: 0.0529

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0539

Gnomad4 FIN exome AF: 0.00957

Gnomad4 NFE exome AF: 0.0144

Gnomad4 OTH exome AF: 0.0300

GnomAD4 genome AF: 0.0536 AC: 8157 AN: 152166 Hom.: 487 Cov.: 33 AF XY: 0.0530 AC XY: 3942 AN XY: 74406

Gnomad4 AFR AF: 0.146

Gnomad4 AMR AF: 0.0271

Gnomad4 ASJ AF: 0.0496

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0459

Gnomad4 FIN AF: 0.00952

Gnomad4 NFE AF: 0.0159

Gnomad4 OTH AF: 0.0478

Alfa AF: 0.0237 Hom.: 172

Bravo AF: 0.0587

TwinsUK AF: 0.0148 AC: 55

ALSPAC AF: 0.0163 AC: 63

ESP6500AA AF: 0.140 AC: 541

ESP6500EA AF: 0.0158 AC: 131

ExAC AF: 0.0321 AC: 3874

Asia WGS AF: 0.0290 AC: 100 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 16, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 04, 2020	This variant is associated with the following publications: (PMID: 27884173, 24193021) -
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	Benign	0.11
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D;D
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;D
MetaRNN	Benign	0.0038	T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Pathogenic	3.0	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.31	T
REVEL	Uncertain	0.34
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;D
Vest4		0.68
MPC		0.24
ClinPred		0.017	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.59
gMVP		0.43

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: rs78394850; hg19: chr1-158592847; COSMIC: COSV63756152; COSMIC: COSV63756152;