NM_005475.3:c.724C>G

Variant names:

• chr12-111418869-C-G
• rs78894077
• NM_005475.3:c.724C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_005475.3(SH2B3):​c.724C>G​(p.Pro242Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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. P242S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SH2B3 NM_005475.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.88
• Publications: 0 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.782

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH2B3	NM_005475.3	c.724C>G	p.Pro242Ala	missense_variant	Exon 2 of 8	ENST00000341259.7	NP_005466.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SH2B3	ENST00000341259.7	c.724C>G	p.Pro242Ala	missense_variant	Exon 2 of 8	1	NM_005475.3	ENSP00000345492.2
SH2B3	ENST00000550925.2	c.529C>G	p.Pro177Ala	missense_variant	Exon 1 of 2	5		ENSP00000473529.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Benign	-0.047	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.028	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Benign	-0.63	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		6.9
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-6.0	D
REVEL	Uncertain	0.30
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.036	D
Polyphen		1.0	D
Vest4		0.62
MutPred		0.53		Loss of catalytic residue at P242 (P = 0.0154);
MVP		0.92
MPC		0.21
ClinPred		0.98	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.33
gMVP		0.59
Mutation Taster		=56/44	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: rs78894077; hg19: chr12-111856673;