NM_001387430.1:c.79C>T

Variant names:

• chr16-28866173-C-T
• rs933512684
• NM_001387430.1:c.79C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001387430.1(SH2B1):​c.79C>T​(p.Arg27Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000031 in 1,516,730 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. R27Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: SH2B1 NM_001387430.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.262
• Publications: 0 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: Genomics England PanelApp, Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.25074342).
• BS2: High AC in GnomAd4 at 8 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH2B1	NM_001387430.1	MANE Select	c.79C>T	p.Arg27Trp	missense	Exon 1 of 8	NP_001374359.1	Q9NRF2-1
	SH2B1	NM_001145795.2		c.79C>T	p.Arg27Trp	missense	Exon 2 of 9	NP_001139267.1	Q9NRF2-1
	SH2B1	NM_001308293.2		c.79C>T	p.Arg27Trp	missense	Exon 4 of 11	NP_001295222.1	Q9NRF2-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH2B1	ENST00000684370.1	MANE Select	c.79C>T	p.Arg27Trp	missense	Exon 1 of 8	ENSP00000507475.1	Q9NRF2-1
	SH2B1	ENST00000618521.4	TSL:1	c.79C>T	p.Arg27Trp	missense	Exon 2 of 9	ENSP00000481709.1	Q9NRF2-1
	SH2B1	ENST00000359285.10	TSL:1	c.79C>T	p.Arg27Trp	missense	Exon 2 of 10	ENSP00000352232.5	Q9NRF2-3

Frequencies

GnomAD3 genomes AF: 0.0000595 AC: 9 AN: 151316 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000198

Gnomad SAS AF: 0.000210

Gnomad FIN AF: 0.0000955

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000590

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.0000428 AC: 7 AN: 163580 AF XY: 0.0000556

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000381

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000162

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000306

Gnomad OTH exome AF: 0.000225

GnomAD4 exome AF: 0.0000286 AC: 39 AN: 1365306 Hom.: 0 Cov.: 37 AF XY: 0.0000340 AC XY: 23 AN XY: 675754

African (AFR) AF: 0.0000325 AC: 1 AN: 30778

American (AMR) AF: 0.0000552 AC: 2 AN: 36250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23606

East Asian (EAS) AF: 0.0000899 AC: 3 AN: 33382

South Asian (SAS) AF: 0.0000374 AC: 3 AN: 80252

European-Finnish (FIN) AF: 0.0000264 AC: 1 AN: 37892

Middle Eastern (MID) AF: 0.000222 AC: 1 AN: 4500

European-Non Finnish (NFE) AF: 0.0000254 AC: 27 AN: 1063352

Other (OTH) AF: 0.0000181 AC: 1 AN: 55294

GnomAD4 genome AF: 0.0000528 AC: 8 AN: 151424 Hom.: 0 Cov.: 32 AF XY: 0.0000541 AC XY: 4 AN XY: 73992

African (AFR) AF: 0.00 AC: 0 AN: 41352

American (AMR) AF: 0.00 AC: 0 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.000198 AC: 1 AN: 5044

South Asian (SAS) AF: 0.000210 AC: 1 AN: 4752

European-Finnish (FIN) AF: 0.0000955 AC: 1 AN: 10470

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000590 AC: 4 AN: 67786

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000227

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	1	-	not specified (1)
-	1	-	SH2B1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.32
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Benign	0.028
Eigen_PC	Benign	0.071
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.26
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Benign	0.21
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.99	D
Vest4		0.49
MutPred		0.49		Loss of phosphorylation at S32 (P = 0.1218)
MVP		0.13
MPC		0.81
ClinPred		0.39	T
GERP RS		3.8
PromoterAI		0.10	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.28
gMVP		0.48
Mutation Taster		=76/24	polymorphism

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: rs933512684; hg19: chr16-28877494;