rs3742601

Variant names:

• chr14-64793825-C-A
• rs3742601
• NM_001355436.2:c.1838G>T

Your query was ambiguous. Multiple possible variants found:

• chr14-64793825-C-A
• chr14-64793825-C-G
• chr14-64793825-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001024858.4(SPTB):​c.1838G>T​(p.Ser613Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00102 in 1,611,054 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00099 (17 hom.)
• Consequence: SPTB NM_001024858.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0270
• Publications: 5 publications found

Genes affected

SPTB (HGNC:11274): (spectrin beta, erythrocytic) This locus encodes a member of the spectrin gene family. Spectrin proteins, along with ankyrin, play a role in cell membrane organization and stability. The protein encoded by this locus functions in stability of erythrocyte membranes, and mutations in this gene have been associated with spherocytosis type 2, hereditary elliptocytosis, and neonatal hemolytic anemia. Alternatively spliced transcript variants have been described. [provided by RefSeq, Nov 2009]

SPTB Gene-Disease associations (from GenCC):

• hereditary spherocytosis type 2

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• elliptocytosis 3

  Inheritance: AR Classification: STRONG Submitted by: 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0066212714).
• BP6: Variant 14-64793825-C-A is Benign according to our data. Variant chr14-64793825-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 257100.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00139 (212/152136) while in subpopulation EAS AF = 0.0171 (88/5154). AF 95% confidence interval is 0.0142. There are 2 homozygotes in GnomAd4. There are 109 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001024858.4. 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
	SPTB	NM_001355436.2	MANE Select	c.1838G>T	p.Ser613Ile	missense	Exon 14 of 36	NP_001342365.1
	SPTB	NM_001024858.4		c.1838G>T	p.Ser613Ile	missense	Exon 13 of 35	NP_001020029.1
	SPTB	NM_001355437.2		c.1838G>T	p.Ser613Ile	missense	Exon 14 of 32	NP_001342366.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTB	ENST00000644917.1	MANE Select	c.1838G>T	p.Ser613Ile	missense	Exon 14 of 36	ENSP00000495909.1
	SPTB	ENST00000389722.7	TSL:2	c.1838G>T	p.Ser613Ile	missense	Exon 13 of 35	ENSP00000374372.3
	SPTB	ENST00000961380.1		c.1838G>T	p.Ser613Ile	missense	Exon 15 of 37	ENSP00000631439.1

Frequencies

GnomAD3 genomes AF: 0.00134 AC: 203 AN: 152008 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00518

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0170

Gnomad SAS AF: 0.00146

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00284 AC: 701 AN: 247250 AF XY: 0.00233

Gnomad AFR exome AF: 0.000372

Gnomad AMR exome AF: 0.00908

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0188

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000358

Gnomad OTH exome AF: 0.00197

GnomAD4 exome AF: 0.000986 AC: 1439 AN: 1458918 Hom.: 17 Cov.: 36 AF XY: 0.000956 AC XY: 694 AN XY: 725974

African (AFR) AF: 0.000209 AC: 7 AN: 33474

American (AMR) AF: 0.00957 AC: 428 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0175 AC: 696 AN: 39700

South Asian (SAS) AF: 0.000591 AC: 51 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000387 AC: 43 AN: 1111912

Other (OTH) AF: 0.00354 AC: 214 AN: 60370

GnomAD4 genome AF: 0.00139 AC: 212 AN: 152136 Hom.: 2 Cov.: 32 AF XY: 0.00147 AC XY: 109 AN XY: 74392

African (AFR) AF: 0.000506 AC: 21 AN: 41524

American (AMR) AF: 0.00524 AC: 80 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0171 AC: 88 AN: 5154

South Asian (SAS) AF: 0.00146 AC: 7 AN: 4800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

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

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68000

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.00123 Hom.: 15

Bravo AF: 0.00196

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00255 AC: 310

Asia WGS AF: 0.0300 AC: 104 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Elliptocytosis (1)
-	-	1	not specified (1)
-	-	1	Spherocytosis, Dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.54	D
Eigen	Benign	-0.078
Eigen_PC	Benign	-0.026
FATHMM_MKL	Benign	0.27	N
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.0066	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.027
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.11
Sift	Benign	0.099	T
Sift4G	Benign	0.14	T
Polyphen		0.29	B
Vest4		0.44
MVP		0.34
MPC		0.57
ClinPred		0.032	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.21
gMVP		0.32
Mutation Taster		=100/0	polymorphism

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: rs3742601; hg19: chr14-65260543;