Variant 19-50428325-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_003121.5(SPIB):c.778C>T(p.Arg260Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000388 in 1,546,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000037 ( 0 hom. )

Consequence

SPIB
NM_003121.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.69

Variant links:

Genes affected

SPIB (HGNC:11242): (Spi-B transcription factor) The protein encoded by this gene is a transcriptional activator that binds to the PU-box (5'-GAGGAA-3') and acts as a lymphoid-specific enhancer. Four transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2011]

SPIB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.17467073).

BS2

High AC in GnomAd at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SPIB	NM_003121.5 linkuse as main transcript	c.778C>T	p.Arg260Cys	missense_variant	6/6	ENST00000595883.6
SPIB	NM_001244000.2 linkuse as main transcript	c.685C>T	p.Arg229Cys	missense_variant	6/6
SPIB	NM_001243998.2 linkuse as main transcript	c.505C>T	p.Arg169Cys	missense_variant	5/5
SPIB	NM_001243999.2 linkuse as main transcript	c.*240C>T		3_prime_UTR_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPIB	ENST00000595883.6 linkuse as main transcript	c.778C>T	p.Arg260Cys	missense_variant	6/6	1	NM_003121.5	P1	Q01892-1
SPIB	ENST00000270632.7 linkuse as main transcript	c.*240C>T		3_prime_UTR_variant	6/6	1			Q01892-2
SPIB	ENST00000439922.6 linkuse as main transcript	c.505C>T	p.Arg169Cys	missense_variant	5/5	2			Q01892-3
SPIB	ENST00000596074.5 linkuse as main transcript	c.*329C>T		3_prime_UTR_variant	5/5	2

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000603

AC:

AN:

149360

Hom.:

AF XY:

0.0000504

AC XY:

AN XY:

79308

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000247

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.000472

GnomAD4 exome

AF:

0.0000373

AC:

AN:

1394754

Hom.:

Cov.:

AF XY:

0.0000349

AC XY:

AN XY:

687614

show subpopulations

Gnomad4 AFR exome

AF:

0.0000634

Gnomad4 AMR exome

AF:

0.000339

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000288

Gnomad4 OTH exome

AF:

0.000121

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000680

Hom.:

Bravo

AF:

0.0000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 08, 2022

The c.778C>T (p.R260C) alteration is located in exon 1 (coding exon 1) of the SPIB gene. This alteration results from a C to T substitution at nucleotide position 778, causing the arginine (R) at amino acid position 260 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.30

Cadd

Uncertain

Dann

Uncertain

0.99

Eigen

Benign

-0.0044

Eigen_PC

Benign

-0.029

FATHMM_MKL

Benign

0.32

LIST_S2

Uncertain

0.91

D;D

M_CAP

Benign

0.064

MetaRNN

Benign

0.17

T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

0.99

D;D

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-2.2

N;.

REVEL

Benign

0.12

Sift

Uncertain

0.0010

D;.

Sift4G

Uncertain

0.0020

D;D

Polyphen

0.99

.;D

Vest4

0.19

MutPred

0.34

.;Loss of MoRF binding (P = 0.0019);

MVP

0.31

MPC

3.1

ClinPred

0.19

GERP RS

4.9

Varity_R

0.14

gMVP

0.96

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over