chr1-158617578-T-C

Variant names:

• chr1-158617578-T-C
• rs111980420
• NM_003126.4:c.6559A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003126.4(SPTA1):​c.6559A>G​(p.Lys2187Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00164 in 1,613,230 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0086 (17 hom., cov: 32)
  • Exomes 𝑓: 0.00091 (20 hom.)
• Consequence: SPTA1 NM_003126.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 3.02
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• hereditary spherocytosis type 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Ambry Genetics
• elliptocytosis 2

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine
• pyropoikilocytosis, hereditary

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• hereditary elliptocytosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary spherocytosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0034264326).
• BP6: Variant 1-158617578-T-C is Benign according to our data. Variant chr1-158617578-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 235335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00861 (1312/152310) while in subpopulation AFR AF = 0.0301 (1250/41568). AF 95% confidence interval is 0.0287. There are 17 homozygotes in GnomAd4. There are 588 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 17 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003126.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTA1	NM_003126.4	MANE Select	c.6559A>G	p.Lys2187Glu	missense	Exon 47 of 52	NP_003117.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTA1	ENST00000643759.2	MANE Select	c.6559A>G	p.Lys2187Glu	missense	Exon 47 of 52	ENSP00000495214.1
	SPTA1	ENST00000492934.1	TSL:2	n.74A>G		non_coding_transcript_exon	Exon 2 of 3
	SPTA1	ENST00000498708.1	TSL:3	n.-10A>G		upstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.00859 AC: 1308 AN: 152192 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.0301

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00575

GnomAD2 exomes AF: 0.00207 AC: 516 AN: 249180 AF XY: 0.00149

Gnomad AFR exome AF: 0.0295

Gnomad AMR exome AF: 0.00131

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000531

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.000908 AC: 1327 AN: 1460920 Hom.: 20 Cov.: 30 AF XY: 0.000772 AC XY: 561 AN XY: 726830

African (AFR) AF: 0.0323 AC: 1081 AN: 33444

American (AMR) AF: 0.00157 AC: 70 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5766

European-Non Finnish (NFE) AF: 0.0000153 AC: 17 AN: 1111206

Other (OTH) AF: 0.00235 AC: 142 AN: 60376

GnomAD4 genome AF: 0.00861 AC: 1312 AN: 152310 Hom.: 17 Cov.: 32 AF XY: 0.00789 AC XY: 588 AN XY: 74490

African (AFR) AF: 0.0301 AC: 1250 AN: 41568

American (AMR) AF: 0.00288 AC: 44 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68028

Other (OTH) AF: 0.00569 AC: 12 AN: 2110

Alfa AF: 0.00318 Hom.: 13

Bravo AF: 0.00969

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0293 AC: 109

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.00251 AC: 303

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Elliptocytosis 2 (1)
-	-	1	Hereditary spherocytosis type 3 (1)
-	-	1	Pyropoikilocytosis, hereditary (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	19
DANN	Benign	0.76
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0034	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		3.0
PrimateAI	Benign	0.47	T
REVEL	Benign	0.042
Sift4G	Benign	0.65	T
Polyphen		0.0030	B
Vest4		0.085
MVP		0.63
MPC		0.042
ClinPred		0.0092	T
GERP RS		4.0
Varity_R		0.086
gMVP		0.18
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs111980420; hg19: chr1-158587368;