19-50423008-G-C

Variant names:

• chr19-50423008-G-C
• rs11546996
• NM_003121.5:c.310G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.797
• Publications: 25 publications found

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]

ENSG00000142539 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 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 VariationId is 769042.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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 rank	MANE	Protein	UniProt
SPIB	NM_003121.5	c.310G>C	p.Ala104Pro	missense_variant	Exon 4 of 6	ENST00000595883.6	NP_003112.2
SPIB	NM_001243999.2	c.310G>C	p.Ala104Pro	missense_variant	Exon 4 of 6		NP_001230928.1
SPIB	NM_001244000.2	c.252G>C	p.Leu84Leu	synonymous_variant	Exon 4 of 6		NP_001230929.2
SPIB	NM_001243998.2	c.66+463G>C		intron_variant	Intron 3 of 4		NP_001230927.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPIB	ENST00000595883.6	c.310G>C	p.Ala104Pro	missense_variant	Exon 4 of 6	1	NM_003121.5	ENSP00000471921.1
ENSG00000142539	ENST00000599632.1	c.712G>C	p.Ala238Pro	missense_variant	Exon 8 of 10	5		ENSP00000473233.1

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

GnomAD2 exomes AF: 0.659 AC: 128155 AN: 194396 AF XY: 0.670

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 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

African (AFR) AF: 0.320 AC: 9698 AN: 30304

American (AMR) AF: 0.657 AC: 21507 AN: 32716

Ashkenazi Jewish (ASJ) AF: 0.659 AC: 14170 AN: 21514

East Asian (EAS) AF: 0.175 AC: 6742 AN: 38486

South Asian (SAS) AF: 0.646 AC: 48754 AN: 75456

European-Finnish (FIN) AF: 0.816 AC: 40758 AN: 49944

Middle Eastern (MID) AF: 0.622 AC: 2884 AN: 4640

European-Non Finnish (NFE) AF: 0.771 AC: 808199 AN: 1048200

Other (OTH) AF: 0.687 AC: 38380 AN: 55898

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

African (AFR) AF: 0.337 AC: 13898 AN: 41258

American (AMR) AF: 0.659 AC: 10032 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.648 AC: 2245 AN: 3462

East Asian (EAS) AF: 0.205 AC: 1047 AN: 5118

South Asian (SAS) AF: 0.610 AC: 2919 AN: 4786

European-Finnish (FIN) AF: 0.831 AC: 8690 AN: 10452

Middle Eastern (MID) AF: 0.620 AC: 181 AN: 292

European-Non Finnish (NFE) AF: 0.763 AC: 51633 AN: 67702

Other (OTH) AF: 0.603 AC: 1265 AN: 2098

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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Oct 30, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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
PhyloP100		0.80
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.46	.;.;N
REVEL	Benign	0.027
Sift	Benign	0.32	.;.;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
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11546996; hg19: chr19-50926265; COSMIC: COSV54530313; COSMIC: COSV54530313;