chr8-55946448-G-A

Position:

chr8-55946448-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2

The NM_002350.4(LYN):c.133G>A(p.Val45Ile) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000162 in 1,603,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

LYN
NM_002350.4 missense, splice_region

Scores

Splicing: ADA: 0.4926

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.47

Variant links:

Genes affected

LYN (HGNC:6735): (LYN proto-oncogene, Src family tyrosine kinase) This gene encodes a tyrosine protein kinase, which maybe involved in the regulation of mast cell degranulation, and erythroid differentiation. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2011]

LYN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), LYN. . Gene score misZ 3.3381 (greater than the threshold 3.09). Trascript score misZ 3.9896 (greater than threshold 3.09). GenCC has associacion of gene with autoinflammatory disease, systemic, with vasculitis.

BP4

Computational evidence support a benign effect (MetaRNN=0.13072911).

BS2

High AC in GnomAdExome4 at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
LYN	NM_002350.4 linkuse as main transcript	c.133G>A	p.Val45Ile	missense_variant, splice_region_variant	3/13	ENST00000519728.6
LYN	NM_001111097.3 linkuse as main transcript	c.70G>A	p.Val24Ile	missense_variant, splice_region_variant	3/13
LYN	XM_011517529.4 linkuse as main transcript	c.-135G>A		splice_region_variant, 5_prime_UTR_variant	2/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LYN	ENST00000519728.6 linkuse as main transcript	c.133G>A	p.Val45Ile	missense_variant, splice_region_variant	3/13	1	NM_002350.4	P4	P07948-1
LYN	ENST00000520220.6 linkuse as main transcript	c.70G>A	p.Val24Ile	missense_variant, splice_region_variant	3/13	1		A1	P07948-2
LYN	ENST00000520050.1 linkuse as main transcript	c.133G>A	p.Val45Ile	missense_variant, splice_region_variant	3/6	4

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000240

AC:

AN:

249914

Hom.:

AF XY:

0.0000370

AC XY:

AN XY:

135290

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000985

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000266

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000165

AC:

AN:

1451600

Hom.:

Cov.:

AF XY:

0.0000207

AC XY:

AN XY:

722966

show subpopulations

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:

0.000151

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000816

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152092

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74286

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 23, 2023

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 45 of the LYN protein (p.Val45Ile). This variant is present in population databases (rs745815088, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with LYN-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.27

T;.;.

Eigen

Benign

-0.059

Eigen_PC

Benign

0.12

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.61

T;T;T

M_CAP

Uncertain

0.091

MetaRNN

Benign

0.12

T;T;T

MetaSVM

Benign

-0.85

MutationAssessor

Benign

0.34

N;.;.

MutationTaster

Benign

0.89

D;N

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.24

N;N;N

REVEL

Benign

0.17

Sift

Benign

0.48

T;T;T

Sift4G

Benign

0.29

T;T;T

Polyphen

0.049

B;.;.

Vest4

0.079

MutPred

0.11

Gain of catalytic residue at L50 (P = 0.0237);.;Gain of catalytic residue at L50 (P = 0.0237);

MVP

0.67

MPC

0.81

ClinPred

0.15

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.059

gMVP

0.12

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.49

dbscSNV1_RF

Benign

0.53

SpliceAI score (max)

0.060

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over