19-50422871-A-G

Variant summary

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

The NM_003121.5(SPIB):c.173A>G(p.Tyr58Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000789 in 1,608,704 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: 𝑓 0.00042 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000043 (0 hom.)
• Consequence: SPIB NM_003121.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.72

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=0.06676015).
• BS2: High AC in GnomAd at 64 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPIB	NM_003121.5	c.173A>G	p.Tyr58Cys	missense_variant	4/6	ENST00000595883.6
SPIB	NM_001244000.2	c.115A>G	p.Met39Val	missense_variant	4/6
SPIB	NM_001243999.2	c.173A>G	p.Tyr58Cys	missense_variant	4/6
SPIB	NM_001243998.2	c.66+326A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPIB	ENST00000595883.6	c.173A>G	p.Tyr58Cys	missense_variant	4/6	1	NM_003121.5	P1

Frequencies

GnomAD3 genomes AF: 0.000424 AC: 64 AN: 150910 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00149

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

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: 0.000481

GnomAD3 exomes AF: 0.000113 AC: 28 AN: 247234 Hom.: 1 AF XY: 0.000127 AC XY: 17 AN XY: 133954

Gnomad AFR exome AF: 0.00131

Gnomad AMR exome AF: 0.0000876

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: 0.0000360

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000432 AC: 63 AN: 1457794 Hom.: 0 Cov.: 31 AF XY: 0.0000345 AC XY: 25 AN XY: 725084

Gnomad4 AFR exome AF: 0.00117

Gnomad4 AMR exome AF: 0.000135

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.0000830

GnomAD4 genome AF: 0.000424 AC: 64 AN: 150910 Hom.: 0 Cov.: 32 AF XY: 0.000408 AC XY: 30 AN XY: 73594

Gnomad4 AFR AF: 0.00149

Gnomad4 AMR AF: 0.000132

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: 0.000481

Alfa AF: 0.000290 Hom.: 0

Bravo AF: 0.000457

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000115 AC: 14

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

Jun 18, 2021

The c.173A>G (p.Y58C) alteration is located in exon 1 (coding exon 1) of the SPIB gene. This alteration results from a A to G substitution at nucleotide position 173, causing the tyrosine (Y) at amino acid position 58 to be replaced by a cysteine (C). 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	Benign	0.12
BayesDel_addAF	Benign	-0.029	T
BayesDel_noAF	Benign	-0.15
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.19	T
M_CAP	Benign	0.084	D
MetaRNN	Benign	0.067	T
MutationTaster	Benign	0.97	D;D
Sift4G	Benign	0.49	T
MVP		0.25
ClinPred		0.084	T
GERP RS		4.2

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: rs145129604; hg19: chr19-50926128;