19-50428175-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003121.5(SPIB):c.628C>A(p.Arg210Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000695 in 1,437,918 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: SPIB NM_003121.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.28

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19883671).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPIB	NM_003121.5	c.628C>A	p.Arg210Ser	missense_variant	6/6	ENST00000595883.6
SPIB	NM_001244000.2	c.535C>A	p.Arg179Ser	missense_variant	6/6
SPIB	NM_001243998.2	c.355C>A	p.Arg119Ser	missense_variant	5/5
SPIB	NM_001243999.2	c.*90C>A		3_prime_UTR_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPIB	ENST00000595883.6	c.628C>A	p.Arg210Ser	missense_variant	6/6	1	NM_003121.5	P1
SPIB	ENST00000270632.7	c.*90C>A		3_prime_UTR_variant	6/6	1
SPIB	ENST00000439922.6	c.355C>A	p.Arg119Ser	missense_variant	5/5	2
SPIB	ENST00000596074.5	c.*179C>A		3_prime_UTR_variant	5/5	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.95e-7 AC: 1 AN: 1437918 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 712956

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: 9.09e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000207 Hom.: 0

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

Aug 02, 2022

The c.628C>A (p.R210S) alteration is located in exon 1 (coding exon 1) of the SPIB gene. This alteration results from a C to A substitution at nucleotide position 628, causing the arginine (R) at amino acid position 210 to be replaced by a serine (S). 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	Pathogenic	0.64
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
Cadd	Pathogenic	30
Dann	Uncertain	1.0
Eigen	Benign	-0.0029
Eigen_PC	Benign	0.091
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.20	T;T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	0.93	D;N
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.1	N;.
REVEL	Benign	0.083
Sift	Benign	0.16	T;.
Sift4G	Benign	0.26	T;T
Polyphen		0.47	.;P
Vest4		0.20
MVP		0.15
MPC		2.8
ClinPred		0.78	D
GERP RS		3.0
Varity_R		0.71
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

Other links and lift over

dbSNP: rs1413323093; hg19: chr19-50931432;