19-50422483-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_003121.5(SPIB):c.62G>A(p.Gly21Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000593 in 1,613,942 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00061 (2 hom.)
• Consequence: SPIB NM_003121.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.49

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012465656).
• BP6: Variant 19-50422483-G-A is Benign according to our data. Variant chr19-50422483-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 778173.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 69 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPIB	NM_003121.5	c.62G>A	p.Gly21Asp	missense_variant	3/6	ENST00000595883.6
SPIB	NM_001244000.2	c.4G>A	p.Ala2Thr	missense_variant	3/6
SPIB	NM_001243999.2	c.62G>A	p.Gly21Asp	missense_variant	3/6
SPIB	NM_001243998.2	c.4G>A	p.Ala2Thr	missense_variant	3/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPIB	ENST00000595883.6	c.62G>A	p.Gly21Asp	missense_variant	3/6	1	NM_003121.5	P1

Frequencies

GnomAD3 genomes AF: 0.000454 AC: 69 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000471

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000661 AC: 166 AN: 251078 Hom.: 2 AF XY: 0.000633 AC XY: 86 AN XY: 135796

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00647

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000784

Gnomad FIN exome AF: 0.0000925

Gnomad NFE exome AF: 0.000502

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.000607 AC: 887 AN: 1461678 Hom.: 2 Cov.: 31 AF XY: 0.000595 AC XY: 433 AN XY: 727138

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.00666

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000661

Gnomad4 FIN exome AF: 0.000262

Gnomad4 NFE exome AF: 0.000500

Gnomad4 OTH exome AF: 0.00104

GnomAD4 genome AF: 0.000460 AC: 70 AN: 152264 Hom.: 0 Cov.: 32 AF XY: 0.000363 AC XY: 27 AN XY: 74442

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00749

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000471

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000918 Hom.: 0

Bravo AF: 0.000510

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000535 AC: 65

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000982

EpiControl AF: 0.000474

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Aug 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.23
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.47	T;T
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.012	T;T
MetaSVM	Benign	-0.86	T
MutationTaster	Benign	0.95	D;N
PROVEAN	Benign	-0.43	N;.
REVEL	Benign	0.032
Sift	Benign	0.095	T;.
Sift4G	Uncertain	0.041	D;T
Vest4		0.24
MVP		0.61
ClinPred		0.063	T
GERP RS		4.4

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs200555920; hg19: chr19-50925740;