chr1-158681595-G-GCAA

Variant names:

• chr1-158681595-G-GCAA
• rs757679761
• NM_003126.4:c.460_462dupTTG

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PS3 PM4_Supporting PP5

The NM_003126.4(SPTA1):​c.460_462dupTTG​(p.Leu154dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000595 in 1,613,826 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV002500695: Experimental evidence revealed a decrease of the alpha l domain of spectrin and presence of an atypical peptide and also, impaired ability to undergo self association to form tetramers and higher oligomers (Lawler_1985, Marchesi_1987).; SCV000710385: Published functional studies on red blood cells extracted from patients with hereditary elliptocytosis (HE) who harbor the c.460_462dupTTG variant, show increased spectrum dimers as compared to wild type red blood cells, suggesting the variant causes a structural defect in the spectrin molecule affecting tetramer formation (PMID:4027386); SCV002049268: "In vitro functional analyses demonstrate impaired SPTA1 oligomer formation (Marchesi et al., 1987)."; SCV002214445: Experimental studies have shown that this variant affects SPTA1 function (PMID:3922449).".

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: SPTA1 NM_003126.4 conservative_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:13 U:1
• Conservation: PhyloP100: -0.00400
• Publications: 7 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: Likely_pathogenic. The variant received 6 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002500695: Experimental evidence revealed a decrease of the alpha l domain of spectrin and presence of an atypical peptide and also, impaired ability to undergo self association to form tetramers and higher oligomers (Lawler_1985, Marchesi_1987).; SCV000710385: Published functional studies on red blood cells extracted from patients with hereditary elliptocytosis (HE) who harbor the c.460_462dupTTG variant, show increased spectrum dimers as compared to wild type red blood cells, suggesting the variant causes a structural defect in the spectrin molecule affecting tetramer formation (PMID: 4027386); SCV002049268: "In vitro functional analyses demonstrate impaired SPTA1 oligomer formation (Marchesi et al., 1987)."; SCV002214445: Experimental studies have shown that this variant affects SPTA1 function (PMID: 3922449).
• PM4: Nonframeshift variant in NON repetitive region in NM_003126.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 1-158681595-G-GCAA is Pathogenic according to our data. Variant chr1-158681595-G-GCAA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 12847.

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.460_462dupTTG	p.Leu154dup	conservative_inframe_insertion	Exon 4 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.460_462dupTTG	p.Leu154dup	conservative_inframe_insertion	Exon 4 of 52	ENSP00000495214.1	P02549-1

Frequencies

GnomAD3 genomes AF: 0.000302 AC: 46 AN: 152124 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.0000763 AC: 19 AN: 249160 AF XY: 0.0000370

Gnomad AFR exome AF: 0.00110

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000342 AC: 50 AN: 1461584 Hom.: 0 Cov.: 32 AF XY: 0.0000330 AC XY: 24 AN XY: 727096

African (AFR) AF: 0.00114 AC: 38 AN: 33448

American (AMR) AF: 0.00 AC: 0 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5762

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111804

Other (OTH) AF: 0.000116 AC: 7 AN: 60374

GnomAD4 genome AF: 0.000302 AC: 46 AN: 152242 Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 20 AN XY: 74438

African (AFR) AF: 0.00108 AC: 45 AN: 41560

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68018

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

Alfa AF: 0.000170 Hom.: 0

Bravo AF: 0.000321

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
7	1	-	not provided (8)
4	-	-	Elliptocytosis 2 (4)
1	-	-	Pyropoikilocytosis, hereditary (1)
1	-	-	SPTA1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.0040
Mutation Taster		=49/51	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs757679761; hg19: chr1-158651385;