12-111406282-G-A

Variant names:

• chr12-111406282-G-A
• rs572454376
• NM_005475.3:c.-28+5G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PP3_Moderate BP6 BS1

The NM_005475.3(SH2B3):​c.-28+5G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00287 in 152,302 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0029 (0 hom., cov: 33)
  • Exomes 𝑓: 0.016 (0 hom.)
• Consequence: SH2B3 NM_005475.3 splice_region, intron
• Scores: Splicing: ADA: 0.9997
• Clinical Significance: Likely benign no assertion criteria provided B:2
• Conservation: PhyloP100: 2.59
• Publications: 3 publications found

Genes affected

SH2B3 (HGNC:29605): (SH2B adaptor protein 3) This gene encodes a member of the SH2B adaptor family of proteins, which are involved in a range of signaling activities by growth factor and cytokine receptors. The encoded protein is a key negative regulator of cytokine signaling and plays a critical role in hematopoiesis. Mutations in this gene have been associated with susceptibility to celiac disease type 13 and susceptibility to insulin-dependent diabetes mellitus. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2014]

SH2B3 Gene-Disease associations (from GenCC):

• acute lymphoblastic leukemia

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
• growth retardation-mild developmental delay-chronic hepatitis syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• primary familial polycythemia due to EPO receptor mutation

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)
• schizophrenia

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)
• thrombocythemia 1

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BP6: Variant 12-111406282-G-A is Benign according to our data. Variant chr12-111406282-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1299799.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00286 (436/152238) while in subpopulation NFE AF = 0.00412 (280/67976). AF 95% confidence interval is 0.00372. There are 0 homozygotes in GnomAd4. There are 211 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH2B3	NM_005475.3	c.-28+5G>A		splice_region_variant, intron_variant	Intron 1 of 7	ENST00000341259.7	NP_005466.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SH2B3	ENST00000341259.7	c.-28+5G>A		splice_region_variant, intron_variant	Intron 1 of 7	1	NM_005475.3	ENSP00000345492.2

Frequencies

GnomAD3 genomes AF: 0.00287 AC: 436 AN: 152124 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0106

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00412

Gnomad OTH AF: 0.00239

GnomAD4 exome AF: 0.0156 AC: 1 AN: 64 Hom.: 0 Cov.: 0 AF XY: 0.0200 AC XY: 1 AN XY: 50

African (AFR) AF: 0.00 AC: 0 AN: 6

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0200 AC: 1 AN: 50

Other (OTH) AF: 0.00 AC: 0 AN: 6

GnomAD4 genome AF: 0.00286 AC: 436 AN: 152238 Hom.: 0 Cov.: 33 AF XY: 0.00284 AC XY: 211 AN XY: 74426

African (AFR) AF: 0.000529 AC: 22 AN: 41572

American (AMR) AF: 0.000588 AC: 9 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.0106 AC: 112 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00412 AC: 280 AN: 67976

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00218 Hom.: 0

Bravo AF: 0.00207

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: no assertion criteria provided

Submissions by phenotype

not provided Benign:2

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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	20
DANN	Uncertain	0.98
PhyloP100		2.6
PromoterAI		-0.42	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.92
SpliceAI score (max)		0.090		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: rs572454376; hg19: chr12-111844086;