rs229581

Variant names:

• chr14-64804932-A-G
• rs229581
• NM_001355436.2:c.300+7T>C

Your query was ambiguous. Multiple possible variants found:

• chr14-64804932-A-G
• chr14-64804932-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001355436.2(SPTB):​c.300+7T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.344 in 1,613,542 control chromosomes in the GnomAD database, including 101,038 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (14818 hom., cov: 32)
  • Exomes 𝑓: 0.34 (86220 hom.)
• Consequence: SPTB NM_001355436.2 splice_region, intron
• Scores: Splicing: ADA: 0.00003127
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.457
• Publications: 6 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: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• elliptocytosis 3

  Inheritance: AR, AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia
• 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 (BayesDel_noAF=-0.91).
• BP6: Variant 14-64804932-A-G is Benign according to our data. Variant chr14-64804932-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 257106.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.631 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001355436.2. 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.300+7T>C		splice_region intron	N/A	NP_001342365.1	P11277-2
	SPTB	NM_001024858.4		c.300+7T>C		splice_region intron	N/A	NP_001020029.1	P11277-2
	SPTB	NM_001355437.2		c.300+7T>C		splice_region intron	N/A	NP_001342366.1	P11277-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTB	ENST00000644917.1	MANE Select	c.300+7T>C		splice_region intron	N/A	ENSP00000495909.1	P11277-2
	SPTB	ENST00000389722.7	TSL:2	c.300+7T>C		splice_region intron	N/A	ENSP00000374372.3	P11277-2
	SPTB	ENST00000961380.1		c.300+7T>C		splice_region intron	N/A	ENSP00000631439.1

Frequencies

GnomAD3 genomes AF: 0.417 AC: 63420 AN: 151970 Hom.: 14792 Cov.: 32

Gnomad AFR AF: 0.637

Gnomad AMI AF: 0.380

Gnomad AMR AF: 0.331

Gnomad ASJ AF: 0.385

Gnomad EAS AF: 0.352

Gnomad SAS AF: 0.488

Gnomad FIN AF: 0.320

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.320

Gnomad OTH AF: 0.413

GnomAD2 exomes AF: 0.359 AC: 89866 AN: 250250 AF XY: 0.363

Gnomad AFR exome AF: 0.646

Gnomad AMR exome AF: 0.269

Gnomad ASJ exome AF: 0.386

Gnomad EAS exome AF: 0.325

Gnomad FIN exome AF: 0.314

Gnomad NFE exome AF: 0.324

Gnomad OTH exome AF: 0.359

GnomAD4 exome AF: 0.336 AC: 490788 AN: 1461454 Hom.: 86220 Cov.: 46 AF XY: 0.341 AC XY: 247739 AN XY: 727052

African (AFR) AF: 0.650 AC: 21738 AN: 33468

American (AMR) AF: 0.280 AC: 12532 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.395 AC: 10316 AN: 26132

East Asian (EAS) AF: 0.336 AC: 13351 AN: 39694

South Asian (SAS) AF: 0.476 AC: 41063 AN: 86242

European-Finnish (FIN) AF: 0.315 AC: 16795 AN: 53384

Middle Eastern (MID) AF: 0.431 AC: 2422 AN: 5622

European-Non Finnish (NFE) AF: 0.315 AC: 350575 AN: 1111834

Other (OTH) AF: 0.364 AC: 21996 AN: 60358

GnomAD4 genome AF: 0.417 AC: 63488 AN: 152088 Hom.: 14818 Cov.: 32 AF XY: 0.416 AC XY: 30947 AN XY: 74352

African (AFR) AF: 0.637 AC: 26449 AN: 41492

American (AMR) AF: 0.330 AC: 5048 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.385 AC: 1334 AN: 3468

East Asian (EAS) AF: 0.351 AC: 1813 AN: 5164

South Asian (SAS) AF: 0.487 AC: 2350 AN: 4822

European-Finnish (FIN) AF: 0.320 AC: 3384 AN: 10576

Middle Eastern (MID) AF: 0.435 AC: 128 AN: 294

European-Non Finnish (NFE) AF: 0.320 AC: 21764 AN: 67968

Other (OTH) AF: 0.413 AC: 873 AN: 2112

Alfa AF: 0.368 Hom.: 4928

Bravo AF: 0.424

Asia WGS AF: 0.446 AC: 1551 AN: 3478

EpiCase AF: 0.337

EpiControl AF: 0.338

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Elliptocytosis (1)
-	-	1	Hereditary spherocytosis type 2 (1)
-	-	1	not specified (1)
-	-	1	Spherocytosis, Dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	6.8
DANN	Benign	0.42
PhyloP100		0.46
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000031
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.090		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: rs229581; hg19: chr14-65271650;