8-55941890-A-G

Position:

• chr8-55941890-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 5P and 2B. PM1 PM2 PP2 BP4_Moderate

The NM_002350.4(LYN):​c.31A>G​(p.Ser11Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,640 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LYN NM_002350.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.35

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 Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a modified_residue Phosphoserine (size 0) in uniprot entity LYN_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• 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=0.087917626).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LYN	NM_002350.4	c.31A>G	p.Ser11Gly	missense_variant	2/13	ENST00000519728.6
LYN	NM_001111097.3	c.31A>G	p.Ser11Gly	missense_variant	2/13
LYN	XM_011517529.4	c.-135-4558A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LYN	ENST00000519728.6	c.31A>G	p.Ser11Gly	missense_variant	2/13	1	NM_002350.4	P4
LYN	ENST00000520220.6	c.31A>G	p.Ser11Gly	missense_variant	2/13	1		A1
LYN	ENST00000520050.1	c.31A>G	p.Ser11Gly	missense_variant	2/6	4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460640 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 726704

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

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

Labcorp Genetics (formerly Invitae), Labcorp

Jun 20, 2022

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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 1007962). This variant has not been reported in the literature in individuals affected with LYN-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 11 of the LYN protein (p.Ser11Gly). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.064	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Benign	0.27	T;.;.
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.69	T;T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.088	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.14	N;N;.
MutationTaster	Benign	0.98	N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.29	N;N;N
REVEL	Benign	0.042
Sift	Benign	0.42	T;T;T
Sift4G	Benign	0.44	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.26
MutPred		0.24		Loss of phosphorylation at S11 (P = 0.0122);Loss of phosphorylation at S11 (P = 0.0122);Loss of phosphorylation at S11 (P = 0.0122);
MVP		0.73
MPC		0.91
ClinPred		0.13	T
GERP RS		3.3
Varity_R		0.082
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs1806621966; hg19: chr8-56854449;