rs11546996

chr19-50423008-G-Achr19-50423008-G-Cchr19-50423008-G-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_003121.5(SPIB):c.310G>A(p.Ala104Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000181 in 1,523,970 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. 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. A104P) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00075 (0 hom., cov: 27)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: SPIB NM_003121.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.797

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013177156).
• BS2: High AC in GnomAd at 113 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPIB	NM_003121.5	c.310G>A	p.Ala104Thr	missense_variant	4/6	ENST00000595883.6
SPIB	NM_001243999.2	c.310G>A	p.Ala104Thr	missense_variant	4/6
SPIB	NM_001244000.2	c.252G>A	p.Leu84=	synonymous_variant	4/6
SPIB	NM_001243998.2	c.66+463G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPIB	ENST00000595883.6	c.310G>A	p.Ala104Thr	missense_variant	4/6	1	NM_003121.5	P1

Frequencies

GnomAD3 genomes AF: 0.000747 AC: 113 AN: 151314 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.00260

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000394

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000360 AC: 70 AN: 194396 Hom.: 0 AF XY: 0.000282 AC XY: 30 AN XY: 106480

Gnomad AFR exome AF: 0.00256

Gnomad AMR exome AF: 0.00139

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: 0.00

Gnomad OTH exome AF: 0.000222

GnomAD4 exome AF: 0.000119 AC: 163 AN: 1372538 Hom.: 0 Cov.: 27 AF XY: 0.000114 AC XY: 77 AN XY: 678316

Gnomad4 AFR exome AF: 0.00357

Gnomad4 AMR exome AF: 0.00122

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: 0.00000659

Gnomad4 OTH exome AF: 0.000124

GnomAD4 genome AF: 0.000746 AC: 113 AN: 151432 Hom.: 0 Cov.: 27 AF XY: 0.000771 AC XY: 57 AN XY: 73958

Gnomad4 AFR AF: 0.00259

Gnomad4 AMR AF: 0.000394

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000112 Hom.: 4146

ExAC AF: 0.000341 AC: 41

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.65
Cadd	Benign	4.2
Dann	Benign	0.58
DEOGEN2	Benign	0.050	T;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.69	T;T;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.013	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.39	T
Sift4G	Benign	0.50	T;T;T
Polyphen		0.0	B;.;B
Vest4		0.056
MVP		0.31
MPC		0.023
ClinPred		0.0030	T
GERP RS		-2.1
Varity_R		0.036
gMVP		0.16

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: rs11546996; hg19: chr19-50926265;