16-28871920-A-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

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 frequency of 0.00000684 in 146,200 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign 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. T484G) has been classified as Uncertain significance.

• 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: 248 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: AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.026253998).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001387430.1. 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
	SH2B1	NM_001387430.1	MANE Select	c.1450A>T	p.Thr484Ser	missense	Exon 5 of 8	NP_001374359.1
	SH2B1	NM_001145795.2		c.1450A>T	p.Thr484Ser	missense	Exon 6 of 9	NP_001139267.1
	SH2B1	NM_001308293.2		c.1450A>T	p.Thr484Ser	missense	Exon 8 of 11	NP_001295222.1

Ensembl Transcripts

Selected	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	ENSP00000507475.1
	SH2B1	ENST00000618521.4	TSL:1	c.1450A>T	p.Thr484Ser	missense	Exon 6 of 9	ENSP00000481709.1
	SH2B1	ENST00000359285.10	TSL:1	c.1450A>T	p.Thr484Ser	missense	Exon 6 of 10	ENSP00000352232.5

Frequencies

GnomAD3 genomes AF: 0.00000684 AC: 1 AN: 146200 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000213

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1423016 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 709210

African (AFR) AF: 0.00 AC: 0 AN: 32490

American (AMR) AF: 0.00 AC: 0 AN: 44296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25170

East Asian (EAS) AF: 0.00 AC: 0 AN: 35652

South Asian (SAS) AF: 0.00 AC: 0 AN: 85580

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5568

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1084224

Other (OTH) AF: 0.00 AC: 0 AN: 58418

GnomAD4 genome AF: 0.00000684 AC: 1 AN: 146200 Hom.: 0 Cov.: 23 AF XY: 0.0000140 AC XY: 1 AN XY: 71184

African (AFR) AF: 0.00 AC: 0 AN: 39130

American (AMR) AF: 0.00 AC: 0 AN: 14830

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3410

East Asian (EAS) AF: 0.000213 AC: 1 AN: 4684

South Asian (SAS) AF: 0.00 AC: 0 AN: 4440

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9888

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66596

Other (OTH) AF: 0.00 AC: 0 AN: 2020

Alfa AF: 0.00 Hom.: 7523

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
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
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		0.43
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	0.51	N
REVEL	Benign	0.022
Sift	Benign	0.55	T
Sift4G	Benign	0.87	T
Polyphen		0.0	B
Vest4		0.13
MutPred		0.22		Gain of glycosylation at T484 (P = 0.0774)
MVP		0.10
MPC		0.21
ClinPred		0.020	T
GERP RS		3.1
PromoterAI		-0.011	Neutral
Varity_R		0.022
gMVP		0.091

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: rs7498665; hg19: chr16-28883241;