NM_005475.3:c.622G>T

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_005475.3(SH2B3):​c.622G>T​(p.Glu208*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Affects (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SH2B3 NM_005475.3 stop_gained
• Clinical Significance: Affects no assertion criteria provided O:1
• 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

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.622G>T	p.Glu208*	stop_gained	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>T	p.Glu208*	stop_gained	Exon 2 of 8	ENSP00000345492.2
	SH2B3	ENST00000896496.1		c.622G>T	p.Glu208*	stop_gained	Exon 2 of 8	ENSP00000566555.1
	SH2B3	ENST00000935782.1		c.622G>T	p.Glu208*	stop_gained	Exon 2 of 8	ENSP00000605841.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1326496 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 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: 0.00 AC: 0 AN: 1055104

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

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Affects

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	-	Primary familial polycythemia due to EPO receptor mutation (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.96	D
PhyloP100		6.2
Vest4		0.81
GERP RS		3.9
PromoterAI		0.070	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=11/189	disease causing (fs/PTC)

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;