NM_003126.4:c.867T>C

Variant names:

• chr1-158677780-A-G
• rs12083637
• NM_003126.4:c.867T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003126.4(SPTA1):​c.867T>C​(p.Ser289Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0062 in 1,613,692 control chromosomes in the GnomAD database, including 512 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (255 hom., cov: 31)
  • Exomes 𝑓: 0.0035 (257 hom.)
• Consequence: SPTA1 NM_003126.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.12
• Publications: 4 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 1-158677780-A-G is Benign according to our data. Variant chr1-158677780-A-G is described in ClinVar as Benign. ClinVar VariationId is 258960.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.12 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.109 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.867T>C	p.Ser289Ser	synonymous	Exon 7 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.867T>C	p.Ser289Ser	synonymous	Exon 7 of 52	ENSP00000495214.1	P02549-1

Frequencies

GnomAD3 genomes AF: 0.0320 AC: 4874 AN: 152078 Hom.: 254 Cov.: 31

Gnomad AFR AF: 0.112

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0103

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.0244

GnomAD2 exomes AF: 0.00847 AC: 2109 AN: 249064 AF XY: 0.00624

Gnomad AFR exome AF: 0.118

Gnomad AMR exome AF: 0.00586

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000239

Gnomad OTH exome AF: 0.00580

GnomAD4 exome AF: 0.00350 AC: 5120 AN: 1461496 Hom.: 257 Cov.: 61 AF XY: 0.00295 AC XY: 2143 AN XY: 727060

African (AFR) AF: 0.122 AC: 4096 AN: 33448

American (AMR) AF: 0.00604 AC: 270 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.000522 AC: 45 AN: 86252

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53410

Middle Eastern (MID) AF: 0.00677 AC: 39 AN: 5764

European-Non Finnish (NFE) AF: 0.000184 AC: 205 AN: 1111752

Other (OTH) AF: 0.00767 AC: 463 AN: 60368

GnomAD4 genome AF: 0.0321 AC: 4881 AN: 152196 Hom.: 255 Cov.: 31 AF XY: 0.0304 AC XY: 2259 AN XY: 74414

African (AFR) AF: 0.112 AC: 4631 AN: 41502

American (AMR) AF: 0.0103 AC: 157 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.000500 AC: 34 AN: 68012

Other (OTH) AF: 0.0241 AC: 51 AN: 2116

Alfa AF: 0.0125 Hom.: 155

Bravo AF: 0.0369

Asia WGS AF: 0.00722 AC: 25 AN: 3478

EpiCase AF: 0.000818

EpiControl AF: 0.000652

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	4.1
DANN	Benign	0.41
PhyloP100		-1.1
Mutation Taster		=99/1	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: rs12083637; hg19: chr1-158647570;