NM_005475.3:c.89G>A

Variant names:

• chr12-111418234-G-A
• rs1871229237
• NM_005475.3:c.89G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_005475.3(SH2B3):​c.89G>A​(p.Cys30Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000702 in 1,424,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C30R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: SH2B3 NM_005475.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.22
• 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):

• syndromic disease

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia
• 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_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH2B3	NM_005475.3	MANE Select	c.89G>A	p.Cys30Tyr	missense	Exon 2 of 8	NP_005466.1	Q9UQQ2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH2B3	ENST00000341259.7	TSL:1 MANE Select	c.89G>A	p.Cys30Tyr	missense	Exon 2 of 8	ENSP00000345492.2	Q9UQQ2
	SH2B3	ENST00000896496.1		c.89G>A	p.Cys30Tyr	missense	Exon 2 of 8	ENSP00000566555.1
	SH2B3	ENST00000935782.1		c.89G>A	p.Cys30Tyr	missense	Exon 2 of 8	ENSP00000605841.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.02e-7 AC: 1 AN: 1424870 Hom.: 0 Cov.: 33 AF XY: 0.00000141 AC XY: 1 AN XY: 708428

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31644

American (AMR) AF: 0.00 AC: 0 AN: 42328

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25448

East Asian (EAS) AF: 0.00 AC: 0 AN: 38064

South Asian (SAS) AF: 0.00 AC: 0 AN: 83602

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36966

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4638

European-Non Finnish (NFE) AF: 9.07e-7 AC: 1 AN: 1102974

Other (OTH) AF: 0.00 AC: 0 AN: 59206

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Familial myelofibrosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.88	D
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.58	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		9.2
PrimateAI	Pathogenic	0.96	D
PROVEAN	Pathogenic	-8.8	D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.92		Gain of phosphorylation at C30 (P = 0.0728)
MVP		0.98
MPC		2.3
ClinPred		0.99	D
GERP RS		4.2
PromoterAI		-0.019	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.88
gMVP		0.84
Mutation Taster		=48/52	disease causing

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: rs1871229237; hg19: chr12-111856038;