1-158677705-A-T

Variant names:

• chr1-158677705-A-T
• rs325996
• NM_003126.4:c.942T>A

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.942T>A​(p.Ala314Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.99 in 1,613,458 control chromosomes in the GnomAD database, including 791,162 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.96 (70132 hom., cov: 31)
  • Exomes 𝑓: 0.99 (721030 hom.)
• Consequence: SPTA1 NM_003126.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.755
• 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, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• elliptocytosis 2

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Ambry Genetics
• pyropoikilocytosis, hereditary

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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=-0.72).
• BP6: Variant 1-158677705-A-T is Benign according to our data. Variant chr1-158677705-A-T is described in ClinVar as Benign. ClinVar VariationId is 258962.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.755 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.991 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.942T>A	p.Ala314Ala	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.942T>A	p.Ala314Ala	synonymous	Exon 7 of 52	ENSP00000495214.1	P02549-1

Frequencies

GnomAD3 genomes AF: 0.958 AC: 145753 AN: 152116 Hom.: 70080 Cov.: 31

Gnomad AFR AF: 0.864

Gnomad AMI AF: 0.970

Gnomad AMR AF: 0.984

Gnomad ASJ AF: 0.998

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.998

Gnomad FIN AF: 0.983

Gnomad MID AF: 0.987

Gnomad NFE AF: 0.997

Gnomad OTH AF: 0.968

GnomAD2 exomes AF: 0.987 AC: 245357 AN: 248620 AF XY: 0.989

Gnomad AFR exome AF: 0.858

Gnomad AMR exome AF: 0.992

Gnomad ASJ exome AF: 0.999

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.985

Gnomad NFE exome AF: 0.996

Gnomad OTH exome AF: 0.993

GnomAD4 exome AF: 0.993 AC: 1451278 AN: 1461224 Hom.: 721030 Cov.: 62 AF XY: 0.994 AC XY: 722435 AN XY: 726914

African (AFR) AF: 0.862 AC: 28815 AN: 33444

American (AMR) AF: 0.990 AC: 44194 AN: 44628

Ashkenazi Jewish (ASJ) AF: 0.999 AC: 26088 AN: 26118

East Asian (EAS) AF: 1.00 AC: 39671 AN: 39672

South Asian (SAS) AF: 0.999 AC: 86177 AN: 86236

European-Finnish (FIN) AF: 0.986 AC: 52599 AN: 53346

Middle Eastern (MID) AF: 0.988 AC: 5697 AN: 5764

European-Non Finnish (NFE) AF: 0.997 AC: 1108407 AN: 1111668

Other (OTH) AF: 0.988 AC: 59630 AN: 60348

GnomAD4 genome AF: 0.958 AC: 145862 AN: 152234 Hom.: 70132 Cov.: 31 AF XY: 0.960 AC XY: 71456 AN XY: 74420

African (AFR) AF: 0.864 AC: 35891 AN: 41526

American (AMR) AF: 0.984 AC: 15029 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.998 AC: 3465 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5162 AN: 5162

South Asian (SAS) AF: 0.998 AC: 4820 AN: 4828

European-Finnish (FIN) AF: 0.983 AC: 10444 AN: 10620

Middle Eastern (MID) AF: 0.983 AC: 289 AN: 294

European-Non Finnish (NFE) AF: 0.997 AC: 67827 AN: 68028

Other (OTH) AF: 0.969 AC: 2050 AN: 2116

Alfa AF: 0.990 Hom.: 18986

Bravo AF: 0.954

Asia WGS AF: 0.993 AC: 3453 AN: 3478

EpiCase AF: 0.998

EpiControl AF: 0.998

ClinVar

ClinVar submissions as Germline

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	-0.72
CADD	Benign	3.6
DANN	Benign	0.68
PhyloP100		-0.76
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs325996; hg19: chr1-158647495; COSMIC: COSV108215570;