rs7498665

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001387430.1(SH2B1):ā€‹c.1450A>Gā€‹(p.Thr484Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.376 in 1,565,774 control chromosomes in the GnomAD database, including 114,338 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (ā˜…ā˜…). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. 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: š‘“ 0.35 ( 9276 hom., cov: 23)
Exomes š‘“: 0.38 ( 105062 hom. )

Consequence

SH2B1
NM_001387430.1 missense

Scores

1
17

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.432
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=6.3735247E-4).
BP6
Variant 16-28871920-A-G is Benign according to our data. Variant chr16-28871920-A-G is described in ClinVar as [Benign]. Clinvar id is 1232867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.4 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SH2B1NM_001387430.1 linkuse as main transcriptc.1450A>G p.Thr484Ala missense_variant 5/8 ENST00000684370.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SH2B1ENST00000684370.1 linkuse as main transcriptc.1450A>G p.Thr484Ala missense_variant 5/8 NM_001387430.1 P3Q9NRF2-1

Frequencies

GnomAD3 genomes
AF:
0.346
AC:
50546
AN:
146026
Hom.:
9247
Cov.:
23
show subpopulations
Gnomad AFR
AF:
0.270
Gnomad AMI
AF:
0.242
Gnomad AMR
AF:
0.408
Gnomad ASJ
AF:
0.270
Gnomad EAS
AF:
0.124
Gnomad SAS
AF:
0.227
Gnomad FIN
AF:
0.433
Gnomad MID
AF:
0.234
Gnomad NFE
AF:
0.395
Gnomad OTH
AF:
0.309
GnomAD3 exomes
AF:
0.351
AC:
87551
AN:
249400
Hom.:
17007
AF XY:
0.343
AC XY:
46316
AN XY:
134960
show subpopulations
Gnomad AFR exome
AF:
0.270
Gnomad AMR exome
AF:
0.488
Gnomad ASJ exome
AF:
0.275
Gnomad EAS exome
AF:
0.102
Gnomad SAS exome
AF:
0.229
Gnomad FIN exome
AF:
0.425
Gnomad NFE exome
AF:
0.388
Gnomad OTH exome
AF:
0.347
GnomAD4 exome
AF:
0.379
AC:
538478
AN:
1419620
Hom.:
105062
Cov.:
30
AF XY:
0.375
AC XY:
265080
AN XY:
707606
show subpopulations
Gnomad4 AFR exome
AF:
0.261
Gnomad4 AMR exome
AF:
0.493
Gnomad4 ASJ exome
AF:
0.278
Gnomad4 EAS exome
AF:
0.141
Gnomad4 SAS exome
AF:
0.228
Gnomad4 FIN exome
AF:
0.436
Gnomad4 NFE exome
AF:
0.400
Gnomad4 OTH exome
AF:
0.352
GnomAD4 genome
AF:
0.346
AC:
50639
AN:
146154
Hom.:
9276
Cov.:
23
AF XY:
0.345
AC XY:
24546
AN XY:
71228
show subpopulations
Gnomad4 AFR
AF:
0.270
Gnomad4 AMR
AF:
0.409
Gnomad4 ASJ
AF:
0.270
Gnomad4 EAS
AF:
0.124
Gnomad4 SAS
AF:
0.227
Gnomad4 FIN
AF:
0.433
Gnomad4 NFE
AF:
0.395
Gnomad4 OTH
AF:
0.313
Alfa
AF:
0.370
Hom.:
5748
Bravo
AF:
0.339
TwinsUK
AF:
0.396
AC:
1468
ALSPAC
AF:
0.401
AC:
1545
ESP6500AA
AF:
0.270
AC:
1188
ESP6500EA
AF:
0.381
AC:
3280
ExAC
AF:
0.345
AC:
41888
Asia WGS
AF:
0.275
AC:
953
AN:
3478
EpiCase
AF:
0.358
EpiControl
AF:
0.354

ClinVar

Significance: Benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:3
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -
Benign, criteria provided, single submitterclinical testingGeneDxJan 19, 2021This variant is associated with the following publications: (PMID: 19079261, 21912638, 23818875, 24971614, 23270367) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.047
BayesDel_addAF
Benign
-0.79
T
BayesDel_noAF
Benign
-0.76
CADD
Benign
15
DANN
Benign
0.34
DEOGEN2
Benign
0.056
T;.;T;T;.;T;.;.
Eigen
Benign
-0.93
Eigen_PC
Benign
-0.75
FATHMM_MKL
Benign
0.0092
N
LIST_S2
Benign
0.014
.;.;T;T;T;T;T;T
MetaRNN
Benign
0.00064
T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.93
T
MutationAssessor
Benign
0.0
N;N;.;N;N;.;N;.
MutationTaster
Benign
1.0
P;P;P;P
PrimateAI
Uncertain
0.53
T
PROVEAN
Benign
0.050
N;N;N;.;N;N;N;N
REVEL
Benign
0.030
Sift
Benign
1.0
T;T;T;.;T;T;T;T
Sift4G
Benign
1.0
T;T;T;T;T;T;T;T
Polyphen
0.0
B;B;B;B;B;B;B;.
Vest4
0.015
MPC
0.23
ClinPred
0.0021
T
GERP RS
3.1
Varity_R
0.018
gMVP
0.13

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs7498665; hg19: chr16-28883241; COSMIC: COSV59461486; COSMIC: COSV59461486; API