10-96204065-G-T

Position:

• chr10-96204065-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_013314.4(BLNK):​c.926C>A​(p.Pro309His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,396 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. P309L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BLNK NM_013314.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.25

Genes affected

BLNK (HGNC:14211): (B cell linker) This gene encodes a cytoplasmic linker or adaptor protein that plays a critical role in B cell development. This protein bridges B cell receptor-associated kinase activation with downstream signaling pathways, thereby affecting various biological functions. The phosphorylation of five tyrosine residues is necessary for this protein to nucleate distinct signaling effectors following B cell receptor activation. Mutations in this gene cause hypoglobulinemia and absent B cells, a disease in which the pro- to pre-B-cell transition is developmentally blocked. Deficiency in this protein has also been shown in some cases of pre-B acute lymphoblastic leukemia. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, May 2012]

ZNF518A (HGNC:29009): (zinc finger protein 518A) The protein encoded by this gene is a member of the krueppel C2H2-type zinc finger protein family. The encoded protein contains five zinc fingers and is likely a nuclear transcriptional regulator. Numerous transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Aug 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34936744).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BLNK	NM_013314.4	c.926C>A	p.Pro309His	missense_variant	13/17	ENST00000224337.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BLNK	ENST00000224337.10	c.926C>A	p.Pro309His	missense_variant	13/17	1	NM_013314.4	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461396 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727024

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Agammaglobulinemia 4, autosomal recessive Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 01, 2019

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with BLNK-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with histidine at codon 309 of the BLNK protein (p.Pro309His). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and histidine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D;.;T;.
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.66
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.83	T;T;T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.35	T;T;T;T
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Uncertain	2.5	M;.;.;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.41	T
PROVEAN	Pathogenic	-4.9	D;D;D;D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.32
MutPred		0.18		Loss of glycosylation at T314 (P = 0.1241);.;.;Loss of glycosylation at T314 (P = 0.1241);
MVP		0.58
MPC		1.1
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.62
gMVP		0.39

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

LitVar

Other links and lift over

dbSNP: rs1177361907; hg19: chr10-97963821;