NM_001715.3:c.974A>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 1P and 7B. PP3BP4_ModerateBP6BS2

The NM_001715.3(BLK):​c.974A>C​(p.Lys325Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00178 in 1,614,070 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K325R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0018 ( 11 hom. )

Consequence

BLK
NM_001715.3 missense

Scores

7
9
3

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 9.11

Publications

9 publications found
Variant links:
Genes affected
BLK (HGNC:1057): (BLK proto-oncogene, Src family tyrosine kinase) This gene encodes a nonreceptor tyrosine-kinase of the src family of proto-oncogenes that are typically involved in cell proliferation and differentiation. The protein has a role in B-cell receptor signaling and B-cell development. The protein also stimulates insulin synthesis and secretion in response to glucose and enhances the expression of several pancreatic beta-cell transcription factors. [provided by RefSeq, Aug 2010]
BLK Gene-Disease associations (from GenCC):
  • maturity-onset diabetes of the young
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • systemic lupus erythematosus
    Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet
  • maturity-onset diabetes of the young type 11
    Inheritance: AD, Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
  • monogenic diabetes
    Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

PP3
Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, Cadd, phyloP100way_vertebrate, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationAssessor, MutationTaster was below the threshold]
BP4
Computational evidence support a benign effect (MetaRNN=0.14501408).
BP6
Variant 8-11557983-A-C is Benign according to our data. Variant chr8-11557983-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 361489.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
BS2
High AC in GnomAd4 at 180 AD,Unknown gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
BLKNM_001715.3 linkc.974A>C p.Lys325Thr missense_variant Exon 10 of 13 ENST00000259089.9 NP_001706.2 P51451Q05D26

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
BLKENST00000259089.9 linkc.974A>C p.Lys325Thr missense_variant Exon 10 of 13 1 NM_001715.3 ENSP00000259089.4 P51451

Frequencies

GnomAD3 genomes
AF:
0.00119
AC:
181
AN:
152188
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000145
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00151
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00249
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00633
Gnomad NFE
AF:
0.00196
Gnomad OTH
AF:
0.00239
GnomAD2 exomes
AF:
0.00170
AC:
427
AN:
251484
AF XY:
0.00190
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.00168
Gnomad ASJ exome
AF:
0.0000992
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000462
Gnomad NFE exome
AF:
0.00240
Gnomad OTH exome
AF:
0.00163
GnomAD4 exome
AF:
0.00184
AC:
2695
AN:
1461764
Hom.:
11
Cov.:
31
AF XY:
0.00190
AC XY:
1381
AN XY:
727192
show subpopulations
African (AFR)
AF:
0.000448
AC:
15
AN:
33478
American (AMR)
AF:
0.00203
AC:
91
AN:
44722
Ashkenazi Jewish (ASJ)
AF:
0.000191
AC:
5
AN:
26130
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39698
South Asian (SAS)
AF:
0.00286
AC:
247
AN:
86254
European-Finnish (FIN)
AF:
0.0000936
AC:
5
AN:
53412
Middle Eastern (MID)
AF:
0.00156
AC:
9
AN:
5766
European-Non Finnish (NFE)
AF:
0.00202
AC:
2248
AN:
1111916
Other (OTH)
AF:
0.00124
AC:
75
AN:
60388
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.471
Heterozygous variant carriers
0
154
307
461
614
768
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
84
168
252
336
420
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.00118
AC:
180
AN:
152306
Hom.:
0
Cov.:
32
AF XY:
0.00111
AC XY:
83
AN XY:
74476
show subpopulations
African (AFR)
AF:
0.000144
AC:
6
AN:
41572
American (AMR)
AF:
0.00150
AC:
23
AN:
15300
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5176
South Asian (SAS)
AF:
0.00249
AC:
12
AN:
4824
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10620
Middle Eastern (MID)
AF:
0.00340
AC:
1
AN:
294
European-Non Finnish (NFE)
AF:
0.00196
AC:
133
AN:
68022
Other (OTH)
AF:
0.00236
AC:
5
AN:
2116
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.501
Heterozygous variant carriers
0
10
20
30
40
50
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
4
8
12
16
20
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00149
Hom.:
1
Bravo
AF:
0.00125
TwinsUK
AF:
0.00162
AC:
6
ALSPAC
AF:
0.00208
AC:
8
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.00140
AC:
12
ExAC
AF:
0.00188
AC:
228
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.00213
EpiControl
AF:
0.00326

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:5
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:2
Jan 12, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Apr 30, 2019
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -

Apr 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

BLK: BS1, BS2 -

not specified Benign:1
Nov 14, 2016
Genetic Services Laboratory, University of Chicago
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Maturity-onset diabetes of the young type 11 Benign:1
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

BLK-related disorder Benign:1
Jun 07, 2019
PreventionGenetics, part of Exact Sciences
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.60
BayesDel_addAF
Uncertain
0.079
D
BayesDel_noAF
Pathogenic
0.34
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.54
D;D;D
Eigen
Uncertain
0.41
Eigen_PC
Uncertain
0.42
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.97
.;D;.
M_CAP
Uncertain
0.20
D
MetaRNN
Benign
0.15
T;T;T
MetaSVM
Uncertain
0.35
D
MutationAssessor
Benign
1.3
.;L;.
PhyloP100
9.1
PrimateAI
Uncertain
0.77
T
PROVEAN
Pathogenic
-5.5
.;D;D
REVEL
Pathogenic
0.83
Sift
Pathogenic
0.0
.;D;D
Sift4G
Uncertain
0.0040
.;D;D
Polyphen
0.49
.;P;.
Vest4
0.86, 0.86
MVP
0.92
MPC
0.067
ClinPred
0.068
T
GERP RS
4.6
Varity_R
0.67
gMVP
0.56
Mutation Taster
=69/31
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
Details are displayed if max score is > 0.2

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

Publications

Other links and lift over

dbSNP: rs77401687; hg19: chr8-11415492; COSMIC: COSV104581002; COSMIC: COSV104581002; API