rs34973695

Variant names:

• chr1-158642966-G-A
• rs34973695
• NM_003126.4:c.4453C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_003126.4(SPTA1):​c.4453C>T​(p.Leu1485Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0233 in 1,613,524 control chromosomes in the GnomAD database, including 524 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.018 (39 hom., cov: 32)
  • Exomes 𝑓: 0.024 (485 hom.)
• Consequence: SPTA1 NM_003126.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:4
• Conservation: PhyloP100: 4.61
• Publications: 8 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009739518).
• BP6: Variant 1-158642966-G-A is Benign according to our data. Variant chr1-158642966-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 258938.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0176 (2677/152166) while in subpopulation SAS AF = 0.0281 (135/4806). AF 95% confidence interval is 0.0258. There are 39 homozygotes in GnomAd4. There are 1271 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 39 AD,AR gene

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.4453C>T	p.Leu1485Phe	missense	Exon 32 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.4453C>T	p.Leu1485Phe	missense	Exon 32 of 52	ENSP00000495214.1	P02549-1

Frequencies

GnomAD3 genomes AF: 0.0176 AC: 2674 AN: 152046 Hom.: 39 Cov.: 32

Gnomad AFR AF: 0.00435

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0145

Gnomad ASJ AF: 0.0406

Gnomad EAS AF: 0.000964

Gnomad SAS AF: 0.0274

Gnomad FIN AF: 0.0126

Gnomad MID AF: 0.0223

Gnomad NFE AF: 0.0268

Gnomad OTH AF: 0.0158

GnomAD2 exomes AF: 0.0198 AC: 4933 AN: 248812 AF XY: 0.0212

Gnomad AFR exome AF: 0.00484

Gnomad AMR exome AF: 0.0130

Gnomad ASJ exome AF: 0.0331

Gnomad EAS exome AF: 0.000167

Gnomad FIN exome AF: 0.0127

Gnomad NFE exome AF: 0.0252

Gnomad OTH exome AF: 0.0204

GnomAD4 exome AF: 0.0239 AC: 34963 AN: 1461358 Hom.: 485 Cov.: 33 AF XY: 0.0243 AC XY: 17630 AN XY: 726964

African (AFR) AF: 0.00290 AC: 97 AN: 33452

American (AMR) AF: 0.0142 AC: 634 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.0340 AC: 887 AN: 26122

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39686

South Asian (SAS) AF: 0.0280 AC: 2411 AN: 86244

European-Finnish (FIN) AF: 0.0128 AC: 684 AN: 53392

Middle Eastern (MID) AF: 0.00938 AC: 54 AN: 5756

European-Non Finnish (NFE) AF: 0.0260 AC: 28870 AN: 1111696

Other (OTH) AF: 0.0219 AC: 1322 AN: 60360

GnomAD4 genome AF: 0.0176 AC: 2677 AN: 152166 Hom.: 39 Cov.: 32 AF XY: 0.0171 AC XY: 1271 AN XY: 74358

African (AFR) AF: 0.00433 AC: 180 AN: 41548

American (AMR) AF: 0.0145 AC: 221 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0406 AC: 141 AN: 3472

East Asian (EAS) AF: 0.000966 AC: 5 AN: 5176

South Asian (SAS) AF: 0.0281 AC: 135 AN: 4806

European-Finnish (FIN) AF: 0.0126 AC: 133 AN: 10580

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0268 AC: 1821 AN: 67990

Other (OTH) AF: 0.0156 AC: 33 AN: 2114

Alfa AF: 0.0238 Hom.: 158

Bravo AF: 0.0173

TwinsUK AF: 0.0235 AC: 87

ALSPAC AF: 0.0249 AC: 96

ESP6500AA AF: 0.00476 AC: 19

ESP6500EA AF: 0.0247 AC: 206

ExAC AF: 0.0194 AC: 2347

Asia WGS AF: 0.0130 AC: 48 AN: 3478

EpiCase AF: 0.0266

EpiControl AF: 0.0272

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	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
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.0097	T
MetaSVM	Uncertain	0.23	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		4.6
PrimateAI	Uncertain	0.48	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.53
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.42
MPC		0.23
ClinPred		0.053	T
GERP RS		5.2
Varity_R		0.59
gMVP		0.30
Mutation Taster		=80/20	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: rs34973695; hg19: chr1-158612756;