rs372733273

Variant names:

• chr14-64766800-G-A
• rs372733273
• NM_001355436.2:c.6271C>T

Your query was ambiguous. Multiple possible variants found:

• chr14-64766800-G-A
• chr14-64766800-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001355436.2(SPTB):​c.6271C>T​(p.Pro2091Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,458,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 19/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P2091T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SPTB NM_001355436.2 missense, splice_region
• Scores: Splicing: ADA: 0.0002932
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.01
• Publications: 1 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08751473).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPTB	NM_001355436.2	c.6271C>T	p.Pro2091Ser	missense_variant, splice_region_variant	Exon 32 of 36	ENST00000644917.1	NP_001342365.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPTB	ENST00000644917.1	c.6271C>T	p.Pro2091Ser	missense_variant, splice_region_variant	Exon 32 of 36		NM_001355436.2	ENSP00000495909.1
SPTB	ENST00000553938.5	c.2266C>T	p.Pro756Ser	missense_variant, splice_region_variant	Exon 13 of 18	1		ENSP00000451324.1
SPTB	ENST00000389722.7	c.6271C>T	p.Pro2091Ser	missense_variant, splice_region_variant	Exon 31 of 35	2		ENSP00000374372.3
SPTB	ENST00000389720.4	c.6271C>T	p.Pro2091Ser	missense_variant, splice_region_variant	Exon 32 of 32	5		ENSP00000374370.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1458858 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725816

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50518

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111940

Other (OTH) AF: 0.0000166 AC: 1 AN: 60358

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000263 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.019	.;.;.;T;T;T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.61	.;.;T;T;.;T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.088	T;T;T;T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.6	L;L;L;.;L;L
PhyloP100		1.0
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.9	N;.;N;N;N;.
REVEL	Benign	0.056
Sift	Benign	0.39	T;.;T;T;T;.
Sift4G	Benign	0.21	T;.;T;T;T;.
Polyphen		0.085	.;.;.;.;B;B
Vest4		0.18
MutPred		0.23		Gain of phosphorylation at P2091 (P = 0.0055);Gain of phosphorylation at P2091 (P = 0.0055);Gain of phosphorylation at P2091 (P = 0.0055);.;Gain of phosphorylation at P2091 (P = 0.0055);Gain of phosphorylation at P2091 (P = 0.0055);
MVP		0.51
MPC		0.20
ClinPred		0.16	T
GERP RS		2.9
Varity_R		0.052
gMVP		0.18
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00029
dbscSNV1_RF	Benign	0.0
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: rs372733273; hg19: chr14-65233518;