19-50423036-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003121.5(SPIB):c.338A>T(p.Gln113Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000796 in 1,256,424 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 27)
  • Exomes 𝑓: 8.0e-7 (0 hom.)
• Consequence: SPIB NM_003121.5 missense, splice_region
• Scores: Splicing: ADA: 0.3259
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.45

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPIB	NM_003121.5	c.338A>T	p.Gln113Leu	missense_variant, splice_region_variant	4/6	ENST00000595883.6
SPIB	NM_001244000.2	c.280A>T	p.Ser94Cys	missense_variant, splice_region_variant	4/6
SPIB	NM_001243999.2	c.338A>T	p.Gln113Leu	missense_variant, splice_region_variant	4/6
SPIB	NM_001243998.2	c.66+491A>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPIB	ENST00000595883.6	c.338A>T	p.Gln113Leu	missense_variant, splice_region_variant	4/6	1	NM_003121.5	P1

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome AF: 7.96e-7 AC: 1 AN: 1256424 Hom.: 0 Cov.: 20 AF XY: 0.00000161 AC XY: 1 AN XY: 619710

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000103

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 27

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 28, 2023

The c.338A>T (p.Q113L) alteration is located in exon 1 (coding exon 1) of the SPIB gene. This alteration results from a A to T substitution at nucleotide position 338, causing the glutamine (Q) at amino acid position 113 to be replaced by a leucine (L). 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	0.13
BayesDel_addAF	Benign	-0.025	T
BayesDel_noAF	Benign	-0.27
Cadd	Pathogenic	27
Dann	Uncertain	0.99
DEOGEN2	Benign	0.20	T;.;.
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.56	T;T;T
M_CAP	Benign	0.035	D
MetaRNN	Uncertain	0.59	D;D;D
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.71	D;D
PrimateAI	Uncertain	0.52	T
Sift4G	Benign	0.37	T;D;T
Polyphen		0.18	B;.;P
Vest4		0.66
MutPred		0.33		Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);
MVP		0.59
MPC		0.028
ClinPred		0.86	D
GERP RS		3.5
Varity_R		0.095
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.33
dbscSNV1_RF	Benign	0.55
SpliceAI score (max)		0.37		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.37		Position offset: 8

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1261613513; hg19: chr19-50926293;