rs75931146

Variant names:

• chr1-158622991-G-A
• rs75931146
• NM_003126.4:c.6112C>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.6112C>T​(p.Leu2038Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0235 in 1,613,796 control chromosomes in the GnomAD database, including 1,304 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.053 (486 hom., cov: 32)
  • Exomes 𝑓: 0.020 (818 hom.)
• Consequence: SPTA1 NM_003126.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 3.47
• Publications: 3 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=-0.53).
• BP6: Variant 1-158622991-G-A is Benign according to our data. Variant chr1-158622991-G-A is described in ClinVar as Benign. ClinVar VariationId is 258952.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.47 with no splicing effect.
• 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.6112C>T	p.Leu2038Leu	synonymous	Exon 43 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.6112C>T	p.Leu2038Leu	synonymous	Exon 43 of 52	ENSP00000495214.1	P02549-1
	SPTA1	ENST00000461624.1	TSL:2	n.658C>T		non_coding_transcript_exon	Exon 5 of 5

Frequencies

GnomAD3 genomes AF: 0.0530 AC: 8067 AN: 152072 Hom.: 484 Cov.: 32

Gnomad AFR AF: 0.145

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0266

Gnomad ASJ AF: 0.0496

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0463

Gnomad FIN AF: 0.00868

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0153

Gnomad OTH AF: 0.0483

GnomAD2 exomes AF: 0.0291 AC: 7267 AN: 249532 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: 0.0204 AC: 29857 AN: 1461606 Hom.: 818 Cov.: 30 AF XY: 0.0212 AC XY: 15430 AN XY: 727124

African (AFR) AF: 0.146 AC: 4895 AN: 33454

American (AMR) AF: 0.0209 AC: 933 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0528 AC: 1381 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0539 AC: 4645 AN: 86252

European-Finnish (FIN) AF: 0.00929 AC: 496 AN: 53418

Middle Eastern (MID) AF: 0.0853 AC: 492 AN: 5766

European-Non Finnish (NFE) AF: 0.0137 AC: 15248 AN: 1111778

Other (OTH) AF: 0.0292 AC: 1765 AN: 60382

GnomAD4 genome AF: 0.0532 AC: 8099 AN: 152190 Hom.: 486 Cov.: 32 AF XY: 0.0527 AC XY: 3918 AN XY: 74404

African (AFR) AF: 0.146 AC: 6041 AN: 41502

American (AMR) AF: 0.0265 AC: 406 AN: 15296

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.0461 AC: 222 AN: 4814

European-Finnish (FIN) AF: 0.00868 AC: 92 AN: 10596

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

European-Non Finnish (NFE) AF: 0.0153 AC: 1041 AN: 68014

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

Alfa AF: 0.0348 Hom.: 130

Bravo AF: 0.0583

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)
-	-	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	-0.53
CADD	Benign	0.69
DANN	Benign	0.36
PhyloP100		3.5
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: rs75931146; hg19: chr1-158592781;