NM_003126.4:c.4605+56A>T

Variant names:

• chr1-158642758-T-A
• rs857721
• NM_003126.4:c.4605+56A>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003126.4(SPTA1):​c.4605+56A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.264 in 1,612,634 control chromosomes in the GnomAD database, including 58,957 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.23 (4728 hom., cov: 31)
  • Exomes 𝑓: 0.27 (54229 hom.)
• Consequence: SPTA1 NM_003126.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0160
• Publications: 30 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.436 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTA1	NM_003126.4	MANE Select	c.4605+56A>T		intron	N/A	NP_003117.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTA1	ENST00000643759.2	MANE Select	c.4605+56A>T		intron	N/A	ENSP00000495214.1
	SPTA1	ENST00000465741.1	TSL:3	n.-226A>T		upstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.231 AC: 35147 AN: 151944 Hom.: 4721 Cov.: 31

Gnomad AFR AF: 0.0956

Gnomad AMI AF: 0.327

Gnomad AMR AF: 0.313

Gnomad ASJ AF: 0.235

Gnomad EAS AF: 0.451

Gnomad SAS AF: 0.184

Gnomad FIN AF: 0.329

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.265

Gnomad OTH AF: 0.254

GnomAD4 exome AF: 0.267 AC: 390174 AN: 1460572 Hom.: 54229 Cov.: 32 AF XY: 0.264 AC XY: 191818 AN XY: 726634

African (AFR) AF: 0.0893 AC: 2985 AN: 33432

American (AMR) AF: 0.357 AC: 15942 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.235 AC: 6126 AN: 26110

East Asian (EAS) AF: 0.408 AC: 16187 AN: 39674

South Asian (SAS) AF: 0.182 AC: 15640 AN: 86164

European-Finnish (FIN) AF: 0.340 AC: 18170 AN: 53390

Middle Eastern (MID) AF: 0.265 AC: 1524 AN: 5758

European-Non Finnish (NFE) AF: 0.267 AC: 297115 AN: 1111076

Other (OTH) AF: 0.273 AC: 16485 AN: 60318

GnomAD4 genome AF: 0.231 AC: 35175 AN: 152062 Hom.: 4728 Cov.: 31 AF XY: 0.236 AC XY: 17529 AN XY: 74336

African (AFR) AF: 0.0957 AC: 3975 AN: 41532

American (AMR) AF: 0.313 AC: 4777 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.235 AC: 816 AN: 3466

East Asian (EAS) AF: 0.451 AC: 2330 AN: 5164

South Asian (SAS) AF: 0.185 AC: 892 AN: 4820

European-Finnish (FIN) AF: 0.329 AC: 3469 AN: 10554

Middle Eastern (MID) AF: 0.279 AC: 81 AN: 290

European-Non Finnish (NFE) AF: 0.265 AC: 17997 AN: 67960

Other (OTH) AF: 0.255 AC: 540 AN: 2114

Alfa AF: 0.246 Hom.: 2749

Bravo AF: 0.230

Asia WGS AF: 0.342 AC: 1184 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.7
DANN	Benign	0.70
PhyloP100		-0.016
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs857721; hg19: chr1-158612548; COSMIC: COSV63750573; COSMIC: COSV63750573;