19-50423008-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003121.5(SPIB):c.310G>C(p.Ala104Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.718 in 1,508,458 control chromosomes in the GnomAD database, including 405,515 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.61 (31479 hom., cov: 27)
  • Exomes 𝑓: 0.73 (374036 hom.)
• Consequence: SPIB NM_003121.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.2879312E-6).
• BP6: Variant 19-50423008-G-C is Benign according to our data. Variant chr19-50423008-G-C is described in ClinVar as [Benign]. Clinvar id is 769042.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.757 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPIB	NM_003121.5	c.310G>C	p.Ala104Pro	missense_variant	4/6	ENST00000595883.6
SPIB	NM_001243999.2	c.310G>C	p.Ala104Pro	missense_variant	4/6
SPIB	NM_001244000.2	c.252G>C	p.Leu84=	synonymous_variant	4/6
SPIB	NM_001243998.2	c.66+463G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPIB	ENST00000595883.6	c.310G>C	p.Ala104Pro	missense_variant	4/6	1	NM_003121.5	P1

Frequencies

GnomAD3 genomes AF: 0.612 AC: 92577 AN: 151182 Hom.: 31478 Cov.: 27

Gnomad AFR AF: 0.337

Gnomad AMI AF: 0.781

Gnomad AMR AF: 0.659

Gnomad ASJ AF: 0.648

Gnomad EAS AF: 0.205

Gnomad SAS AF: 0.611

Gnomad FIN AF: 0.831

Gnomad MID AF: 0.615

Gnomad NFE AF: 0.763

Gnomad OTH AF: 0.600

GnomAD3 exomes AF: 0.659 AC: 128155 AN: 194396 Hom.: 45482 AF XY: 0.670 AC XY: 71336 AN XY: 106480

Gnomad AFR exome AF: 0.322

Gnomad AMR exome AF: 0.649

Gnomad ASJ exome AF: 0.669

Gnomad EAS exome AF: 0.199

Gnomad SAS exome AF: 0.646

Gnomad FIN exome AF: 0.820

Gnomad NFE exome AF: 0.763

Gnomad OTH exome AF: 0.698

GnomAD4 exome AF: 0.730 AC: 991092 AN: 1357158 Hom.: 374036 Cov.: 27 AF XY: 0.728 AC XY: 489006 AN XY: 671262

Gnomad4 AFR exome AF: 0.320

Gnomad4 AMR exome AF: 0.657

Gnomad4 ASJ exome AF: 0.659

Gnomad4 EAS exome AF: 0.175

Gnomad4 SAS exome AF: 0.646

Gnomad4 FIN exome AF: 0.816

Gnomad4 NFE exome AF: 0.771

Gnomad4 OTH exome AF: 0.687

GnomAD4 genome AF: 0.612 AC: 92618 AN: 151300 Hom.: 31479 Cov.: 27 AF XY: 0.614 AC XY: 45353 AN XY: 73878

Gnomad4 AFR AF: 0.337

Gnomad4 AMR AF: 0.659

Gnomad4 ASJ AF: 0.648

Gnomad4 EAS AF: 0.205

Gnomad4 SAS AF: 0.610

Gnomad4 FIN AF: 0.831

Gnomad4 NFE AF: 0.763

Gnomad4 OTH AF: 0.603

Alfa AF: 0.630 Hom.: 4146

Bravo AF: 0.586

ESP6500AA AF: 0.300 AC: 1316

ESP6500EA AF: 0.701 AC: 5995

ExAC AF: 0.653 AC: 78567

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Oct 30, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.65
Cadd	Benign	5.3
Dann	Benign	0.40
DEOGEN2	Benign	0.056	T;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.76	T;T;T
MetaRNN	Benign	0.0000023	T;T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.42	T
Sift4G	Benign	0.25	T;T;T
Polyphen		0.0040	B;.;B
Vest4		0.19
MPC		0.041
ClinPred		0.0039	T
GERP RS		-2.1
Varity_R		0.11
gMVP		0.33

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; COSMIC: COSV54530313; COSMIC: COSV54530313;