chr16-28871920-A-T

Variant names:

• chr16-28871920-A-T
• rs7498665
• NM_001387430.1:c.1450A>T
• SH2B1 p.Thr484Ser

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+1 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 1 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_ModerateB3_Supporting

The NM_001387430.1(SH2B1):c.1450A>T (p.Thr484Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00000684 (AC=1) in the gnomAD database across 146,200 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000213. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. 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: 𝑓 0.0000068 (0 hom., cov: 23)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SH2B1 NM_001387430.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.432
• Publications: 253 publications found

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

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 1 points.

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 = 0.000213, AC = 1 — absent/extremely rare (O3 moderate [+2])
	B3Computational evidence does not support deleterious effect		Computational evidence does not support a deleterious effect; Missense variant — primary computational scorer does not support an oncogenic/deleterious effect; supports B3

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

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	SH2B1 NM_001387430.1	MANE Select	c.1450A>T p.Thr484Ser	missense	Exon 5 of 8	Prot: NP_001374359.1 UniProt:
	SH2B1 NM_001145795.2		c.1450A>T p.Thr484Ser	missense	Exon 6 of 9	Prot: NP_001139267.1 UniProt:
	SH2B1 NM_001308293.2		c.1450A>T p.Thr484Ser	missense	Exon 8 of 11	Prot: NP_001295222.1 UniProt:

SH2B1 NM_001387430.1

MANE Select

HGVSc / HGVSpc.1450A>Tp.Thr484Ser

Exon rankExon 5 of 8

missense

Prot: NP_001374359.1UniProt: Q9NRF2-1

SH2B1 NM_001145795.2

HGVSc / HGVSpc.1450A>Tp.Thr484Ser

Exon rankExon 6 of 9

missense

Prot: NP_001139267.1UniProt: Q9NRF2-1

SH2B1 NM_001308293.2

HGVSc / HGVSpc.1450A>Tp.Thr484Ser

Exon rankExon 8 of 11

missense

Prot: NP_001295222.1UniProt: Q9NRF2-1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	SH2B1 ENST00000684370.1	MANE Select	c.1450A>T p.Thr484Ser	missense	Exon 5 of 8	Prot: ENSP00000507475.1 UniProt:
	SH2B1 ENST00000618521.4	TSL:1	c.1450A>T p.Thr484Ser	missense	Exon 6 of 9	Prot: ENSP00000481709.1 UniProt:
	SH2B1 ENST00000359285.10	TSL:1	c.1450A>T p.Thr484Ser	missense	Exon 6 of 10	Prot: ENSP00000352232.5 UniProt:

SH2B1 ENST00000684370.1

MANE Select

HGVSc / HGVSpc.1450A>Tp.Thr484Ser

Exon rankExon 5 of 8

missense

Prot: ENSP00000507475.1UniProt: Q9NRF2-1

SH2B1 ENST00000618521.4

TSL:1

HGVSc / HGVSpc.1450A>Tp.Thr484Ser

Exon rankExon 6 of 9

missense

Prot: ENSP00000481709.1UniProt: Q9NRF2-1

SH2B1 ENST00000359285.10

TSL:1

HGVSc / HGVSpc.1450A>Tp.Thr484Ser

Exon rankExon 6 of 10

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 4 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.00000684	AC:1	Hom:0	AN:146200	Cov:23
GnomAD4 exome Warning	AF: 0.00	AC:0	Hom:0	AN:1423016	Cov:30
GnomAD4 genome	AF: 0.00000684	AC:1	Hom:0	AN:146200	Cov:23
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:8150	AN:121454	Cov:

Showing 4 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	16
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	17
DANN	Benign	0.92
DEOGEN2	Benign	0.053	T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.21	N
FuncVEP CTI	Benign	0.00073
GPN-Star LLR	N/A	0.75
GPN-Star score	N/A	-0.75
LIST_S2	Benign	0.071	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.026	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	N
PhyloP100	Benign	0.43
popEVE	Benign	-2.7
PrimateAI	Uncertain	0.49	T
PromoterAI	N/A	-0.011	Neutral
PROVEAN	Benign	0.51	N
REVEL	Benign	0.022
Sift	Benign	0.55	T
Sift4G	Benign	0.87	T
Varity_R	N/A	0.022
VESM-3B	Benign	-1.9

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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.

Other links and lift over

dbSNP: rs7498665;

hg19: chr16-28883241;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar