rs202080221

Variant names:

• chr12-111418767-G-A
• rs202080221
• NM_005475.3:c.622G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-111418767-G-A
• chr12-111418767-G-C
• chr12-111418767-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The ENST00000341259.7(SH2B3):​c.622G>A​(p.Glu208Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000302 in 1,326,496 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E208Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000030 (0 hom.)
• Consequence: SH2B3 ENST00000341259.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.24
• Publications: 30 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000341259.7. 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.622G>A	p.Glu208Lys	missense	Exon 2 of 8	NP_005466.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH2B3	ENST00000341259.7	TSL:1 MANE Select	c.622G>A	p.Glu208Lys	missense	Exon 2 of 8	ENSP00000345492.2
	SH2B3	ENST00000550925.2	TSL:5	c.427G>A	p.Glu143Lys	missense	Exon 1 of 2	ENSP00000473529.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000302 AC: 4 AN: 1326496 Hom.: 0 Cov.: 32 AF XY: 0.00000306 AC XY: 2 AN XY: 654562

African (AFR) AF: 0.00 AC: 0 AN: 26158

American (AMR) AF: 0.00 AC: 0 AN: 26958

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22860

East Asian (EAS) AF: 0.00 AC: 0 AN: 29372

South Asian (SAS) AF: 0.00 AC: 0 AN: 73758

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33534

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3922

European-Non Finnish (NFE) AF: 0.00000379 AC: 4 AN: 1055104

Other (OTH) AF: 0.00 AC: 0 AN: 54830

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.090	T
BayesDel_noAF	Benign	-0.37
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.40	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		6.2
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.15
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.032	D
Polyphen		1.0	D
Vest4		0.44
MutPred		0.38		Gain of MoRF binding (P = 0.0049)
MVP		0.86
MPC		1.3
ClinPred		0.95	D
GERP RS		3.9
PromoterAI		0.055	Neutral
Varity_R		0.30
gMVP		0.45
Mutation Taster		=60/40	polymorphism

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: rs202080221; hg19: chr12-111856571;