rs435080

Variant names:

• chr1-158685246-G-A
• rs435080
• NM_003126.4:c.126C>T

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.126C>T​(p.Val42Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.995 in 1,613,794 control chromosomes in the GnomAD database, including 799,329 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.97 (72254 hom., cov: 31)
  • Exomes 𝑓: 1.0 (727075 hom.)
• Consequence: SPTA1 NM_003126.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.307
• Publications: 18 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=-0.52).
• BP6: Variant 1-158685246-G-A is Benign according to our data. Variant chr1-158685246-G-A is described in ClinVar as Benign. ClinVar VariationId is 258916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.307 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.994 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.126C>T	p.Val42Val	synonymous	Exon 2 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.126C>T	p.Val42Val	synonymous	Exon 2 of 52	ENSP00000495214.1	P02549-1

Frequencies

GnomAD3 genomes AF: 0.974 AC: 148054 AN: 152020 Hom.: 72200 Cov.: 31

Gnomad AFR AF: 0.910

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.989

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.999

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.997

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.977

GnomAD2 exomes AF: 0.993 AC: 245244 AN: 246954 AF XY: 0.995

Gnomad AFR exome AF: 0.906

Gnomad AMR exome AF: 0.995

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.997

GnomAD4 exome AF: 0.997 AC: 1457747 AN: 1461656 Hom.: 727075 Cov.: 71 AF XY: 0.998 AC XY: 725429 AN XY: 727134

African (AFR) AF: 0.910 AC: 30439 AN: 33460

American (AMR) AF: 0.994 AC: 44424 AN: 44702

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 26128 AN: 26128

East Asian (EAS) AF: 1.00 AC: 39694 AN: 39694

South Asian (SAS) AF: 1.00 AC: 86222 AN: 86254

European-Finnish (FIN) AF: 1.00 AC: 53414 AN: 53414

Middle Eastern (MID) AF: 0.990 AC: 5711 AN: 5766

European-Non Finnish (NFE) AF: 1.00 AC: 1111722 AN: 1111856

Other (OTH) AF: 0.994 AC: 59993 AN: 60382

GnomAD4 genome AF: 0.974 AC: 148165 AN: 152138 Hom.: 72254 Cov.: 31 AF XY: 0.975 AC XY: 72545 AN XY: 74390

African (AFR) AF: 0.910 AC: 37746 AN: 41480

American (AMR) AF: 0.989 AC: 15091 AN: 15264

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5160 AN: 5160

South Asian (SAS) AF: 0.999 AC: 4819 AN: 4824

European-Finnish (FIN) AF: 1.00 AC: 10622 AN: 10622

Middle Eastern (MID) AF: 0.993 AC: 292 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 67987 AN: 67998

Other (OTH) AF: 0.977 AC: 2064 AN: 2112

Alfa AF: 0.987 Hom.: 55067

Bravo AF: 0.970

Asia WGS AF: 0.995 AC: 3459 AN: 3476

EpiCase AF: 1.00

EpiControl AF: 1.00

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	3.8
DANN	Benign	0.92
PhyloP100		-0.31
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs435080; hg19: chr1-158655036; COSMIC: COSV108215571;