8-55946448-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

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

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• PP2: Missense variant where missense usually causes diseases, LYN
• BP4: Computational evidence support a benign effect (MetaRNN=0.13072911).
• BS2: High AC in GnomAdExome at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LYN	NM_002350.4	c.133G>A	p.Val45Ile	missense_variant, splice_region_variant	3/13	ENST00000519728.6
LYN	NM_001111097.3	c.70G>A	p.Val24Ile	missense_variant, splice_region_variant	3/13
LYN	XM_011517529.4	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	c.133G>A	p.Val45Ile	missense_variant, splice_region_variant	3/13	1	NM_002350.4	P4
LYN	ENST00000520220.6	c.70G>A	p.Val24Ile	missense_variant, splice_region_variant	3/13	1		A1
LYN	ENST00000520050.1	c.133G>A	p.Val45Ile	missense_variant, splice_region_variant	3/6	4

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152092 Hom.: 0 Cov.: 33

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: 6 AN: 249914 Hom.: 0 AF XY: 0.0000370 AC XY: 5 AN XY: 135290

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: 24 AN: 1451600 Hom.: 0 Cov.: 28 AF XY: 0.0000207 AC XY: 15 AN XY: 722966

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: 2 AN: 152092 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74286

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: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

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	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	19
Dann	Benign	0.97
DEOGEN2	Benign	0.27	T;.;.
Eigen	Benign	-0.059
Eigen_PC	Benign	0.12
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.61	T;T;T
M_CAP	Uncertain	0.091	D
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.34	N;.;.
MutationTaster	Benign	0.89	D;N
PrimateAI	Benign	0.33	T
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	T
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

Other links and lift over

dbSNP: rs745815088; hg19: chr8-56859007;