12-111411711-G-T

Variant names:

• chr12-111411711-G-T
• rs7309325
• NM_005475.3:c.-28+5434G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005475.3(SH2B3):​c.-28+5434G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.379 in 152,038 control chromosomes in the GnomAD database, including 15,034 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.38 (15034 hom., cov: 32)
• Consequence: SH2B3 NM_005475.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.945
• Publications: 10 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.877 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005475.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH2B3	NM_005475.3	MANE Select	c.-28+5434G>T		intron	N/A	NP_005466.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH2B3	ENST00000341259.7	TSL:1 MANE Select	c.-28+5434G>T		intron	N/A	ENSP00000345492.2

Frequencies

GnomAD3 genomes AF: 0.379 AC: 57530 AN: 151920 Hom.: 14996 Cov.: 32

Gnomad AFR AF: 0.685

Gnomad AMI AF: 0.151

Gnomad AMR AF: 0.335

Gnomad ASJ AF: 0.118

Gnomad EAS AF: 0.899

Gnomad SAS AF: 0.372

Gnomad FIN AF: 0.182

Gnomad MID AF: 0.389

Gnomad NFE AF: 0.211

Gnomad OTH AF: 0.361

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.379 AC: 57632 AN: 152038 Hom.: 15034 Cov.: 32 AF XY: 0.378 AC XY: 28109 AN XY: 74326

African (AFR) AF: 0.686 AC: 28414 AN: 41436

American (AMR) AF: 0.335 AC: 5122 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.118 AC: 410 AN: 3466

East Asian (EAS) AF: 0.898 AC: 4637 AN: 5162

South Asian (SAS) AF: 0.372 AC: 1794 AN: 4818

European-Finnish (FIN) AF: 0.182 AC: 1929 AN: 10604

Middle Eastern (MID) AF: 0.384 AC: 113 AN: 294

European-Non Finnish (NFE) AF: 0.211 AC: 14319 AN: 67950

Other (OTH) AF: 0.358 AC: 756 AN: 2112

Alfa AF: 0.279 Hom.: 10981

Bravo AF: 0.409

Asia WGS AF: 0.568 AC: 1972 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.12
DANN	Benign	0.45
PhyloP100		-0.94
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: rs7309325; hg19: chr12-111849515;