chr1-158634601-T-C

Variant names:

• chr1-158634601-T-C
• rs16830483
• NM_003126.4:c.5507A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003126.4(SPTA1):​c.5507A>G​(p.Asn1836Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0236 in 1,614,126 control chromosomes in the GnomAD database, including 1,302 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.053 (484 hom., cov: 32)
  • Exomes 𝑓: 0.020 (818 hom.)
• Consequence: SPTA1 NM_003126.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.26
• Publications: 10 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, PanelApp Australia
• elliptocytosis 2

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

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: PanelApp Australia, 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=0.0015079081).
• BP6: Variant 1-158634601-T-C is Benign according to our data. Variant chr1-158634601-T-C is described in ClinVar as Benign. ClinVar VariationId is 258947.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.142 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTA1	NM_003126.4	MANE Select	c.5507A>G	p.Asn1836Ser	missense	Exon 39 of 52	NP_003117.2	P02549-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTA1	ENST00000643759.2	MANE Select	c.5507A>G	p.Asn1836Ser	missense	Exon 39 of 52	ENSP00000495214.1	P02549-1
	SPTA1	ENST00000461624.1	TSL:2	n.53A>G		non_coding_transcript_exon	Exon 1 of 5

Frequencies

GnomAD3 genomes AF: 0.0530 AC: 8063 AN: 152154 Hom.: 482 Cov.: 32

Gnomad AFR AF: 0.145

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0268

Gnomad ASJ AF: 0.0496

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0459

Gnomad FIN AF: 0.00885

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0153

Gnomad OTH AF: 0.0483

GnomAD2 exomes AF: 0.0291 AC: 7267 AN: 249390 AF XY: 0.0291

Gnomad AFR exome AF: 0.144

Gnomad AMR exome AF: 0.0198

Gnomad ASJ exome AF: 0.0517

Gnomad EAS exome AF: 0.000278

Gnomad FIN exome AF: 0.00812

Gnomad NFE exome AF: 0.0171

Gnomad OTH exome AF: 0.0297

GnomAD4 exome AF: 0.0205 AC: 29927 AN: 1461854 Hom.: 818 Cov.: 32 AF XY: 0.0213 AC XY: 15462 AN XY: 727222

African (AFR) AF: 0.146 AC: 4904 AN: 33476

American (AMR) AF: 0.0209 AC: 933 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0529 AC: 1382 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39694

South Asian (SAS) AF: 0.0539 AC: 4647 AN: 86258

European-Finnish (FIN) AF: 0.00929 AC: 496 AN: 53402

Middle Eastern (MID) AF: 0.0855 AC: 493 AN: 5768

European-Non Finnish (NFE) AF: 0.0138 AC: 15300 AN: 1112008

Other (OTH) AF: 0.0293 AC: 1770 AN: 60396

GnomAD4 genome AF: 0.0532 AC: 8095 AN: 152272 Hom.: 484 Cov.: 32 AF XY: 0.0525 AC XY: 3910 AN XY: 74454

African (AFR) AF: 0.145 AC: 6034 AN: 41516

American (AMR) AF: 0.0267 AC: 409 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0496 AC: 172 AN: 3470

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

South Asian (SAS) AF: 0.0457 AC: 220 AN: 4816

European-Finnish (FIN) AF: 0.00885 AC: 94 AN: 10624

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0153 AC: 1041 AN: 68036

Other (OTH) AF: 0.0478 AC: 101 AN: 2114

Alfa AF: 0.0305 Hom.: 724

Bravo AF: 0.0583

TwinsUK AF: 0.0135 AC: 50

ALSPAC AF: 0.0143 AC: 55

ESP6500AA AF: 0.139 AC: 544

ESP6500EA AF: 0.0151 AC: 125

ExAC AF: 0.0316 AC: 3825

Asia WGS AF: 0.0290 AC: 100 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	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	0.053
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	11
DANN	Benign	0.89
DEOGEN2	Benign	0.29	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.20	N
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.18	N
PhyloP100		1.3
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.074
Sift	Benign	0.68	T
Sift4G	Benign	0.78	T
Polyphen		0.0020	B
Vest4		0.037
MPC		0.025
ClinPred		0.010	T
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.047
gMVP		0.031
Mutation Taster		=89/11	polymorphism (auto)

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

Other links and lift over

dbSNP: rs16830483; hg19: chr1-158604391; COSMIC: COSV63756982; COSMIC: COSV63756982;