Genetic Variant SH2B1:p.Thr484Ser (chr16-28871920-ACA-TCT) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is The variant received 2 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_Moderate

The NM_001387430.1(SH2B1):c.1450_1452delACAinsTCT (p.Thr484Ser) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.T484A: Benign (ClinVar VariationId 1232867, 2 stars); p.T484G: Uncertain_significance (ClinVar VariationId 3350075, 0 stars)

Frequency

Genomes: not found (cov: 23)

Consequence

SH2B1
NM_001387430.1 missense

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.801

Publications

0 publications found

Variant links:

Genes affected

SH2B1 (HGNC:30417): (SH2B adaptor protein 1) This gene encodes a member of the SH2-domain containing mediators family. The encoded protein mediates activation of various kinases and may function in cytokine and growth factor receptor signaling and cellular transformation. Alternatively spliced transcript variants have been described. [provided by RefSeq, Mar 2009]

SH2B1 Gene-Disease associations (from GenCC):

severe early-onset obesity-insulin resistance syndrome due to SH2B1 deficiency
Inheritance: AR, AD Classification: MODERATE, SUPPORTIVE, LIMITED Submitted by: LiferaOmics, Orphanet, Genomics England PanelApp

SH2B1 links:

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new If you want to explore the variant's impact on the transcript NM_001387430.1, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 2 points.

Show applied only (1)

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = absent, AC = 0 — absent/extremely rare (O3 moderate [+2])

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001387430.1. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
SH2B1 NM_001387430.1	MANE Select	c.1450_1452delACAinsTCT p.Thr484Ser	missense	N/A	Prot: NP_001374359.1 UniProt: Q9NRF2-1
SH2B1 NM_001145795.2		c.1450_1452delACAinsTCT p.Thr484Ser	missense	N/A	Prot: NP_001139267.1 UniProt: Q9NRF2-1
SH2B1 NM_001308293.2		c.1450_1452delACAinsTCT p.Thr484Ser	missense	N/A	Prot: NP_001295222.1 UniProt: Q9NRF2-1

SH2B1 NM_001387430.1

MANE Select

HGVSc / HGVSpc.1450_1452delACAinsTCTp.Thr484Ser

Exon rankN/A

missense

Prot: NP_001374359.1UniProt: Q9NRF2-1

SH2B1 NM_001145795.2

HGVSc / HGVSpc.1450_1452delACAinsTCTp.Thr484Ser

Exon rankN/A

missense

Prot: NP_001139267.1UniProt: Q9NRF2-1

SH2B1 NM_001308293.2

HGVSc / HGVSpc.1450_1452delACAinsTCTp.Thr484Ser

Exon rankN/A

missense

Prot: NP_001295222.1UniProt: Q9NRF2-1

Ensembl Transcripts

Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
SH2B1 ENST00000684370.1	MANE Select	c.1450_1452delACAinsTCT p.Thr484Ser	missense	N/A	Prot: ENSP00000507475.1 UniProt: Q9NRF2-1
SH2B1 ENST00000618521.4	TSL:1	c.1450_1452delACAinsTCT p.Thr484Ser	missense	N/A	Prot: ENSP00000481709.1 UniProt: Q9NRF2-1
SH2B1 ENST00000359285.10	TSL:1	c.1450_1452delACAinsTCT p.Thr484Ser	missense	N/A	Prot: ENSP00000352232.5 UniProt: Q9NRF2-3

SH2B1 ENST00000684370.1

MANE Select

HGVSc / HGVSpc.1450_1452delACAinsTCTp.Thr484Ser

Exon rankN/A

missense

Prot: ENSP00000507475.1UniProt: Q9NRF2-1

SH2B1 ENST00000618521.4

TSL:1

HGVSc / HGVSpc.1450_1452delACAinsTCTp.Thr484Ser

Exon rankN/A

missense

Prot: ENSP00000481709.1UniProt: Q9NRF2-1

SH2B1 ENST00000359285.10

TSL:1

HGVSc / HGVSpc.1450_1452delACAinsTCTp.Thr484Ser

Exon rankN/A

missense

Prot: ENSP00000352232.5UniProt: Q9NRF2-3

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:23
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:23

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Benign	0.80

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACGS-UK Somatic Oncogenicity v2025

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational Scores

Splicing Scores

MaveDB functional evidence ?

Publications

Other links and lift over

MaveDB functional evidence