4-4267938-T-C

Position:

• chr4-4267938-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017816.3(LYAR):​c.1091A>G​(p.Lys364Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: LYAR NM_017816.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.66

Genes affected

LYAR (HGNC:26021): (Ly1 antibody reactive) Enables several functions, including DNA-binding transcription factor binding activity; identical protein binding activity; and transcription regulator inhibitor activity. Involved in several processes, including erythrocyte development; negative regulation of innate immune response; and regulation of transcription, DNA-templated. Located in nucleolus and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

LYAR (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12857968).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LYAR	NM_017816.3	c.1091A>G	p.Lys364Arg	missense_variant	10/10	ENST00000343470.9	NP_060286.1
LYAR	NM_001145725.2	c.1091A>G	p.Lys364Arg	missense_variant	10/10		NP_001139197.1
LYAR	XM_011513505.2	c.1091A>G	p.Lys364Arg	missense_variant	10/10		XP_011511807.1
LYAR	XM_011513506.4	c.1091A>G	p.Lys364Arg	missense_variant	9/9		XP_011511808.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LYAR	ENST00000343470.9	c.1091A>G	p.Lys364Arg	missense_variant	10/10	1	NM_017816.3	ENSP00000345917.4
LYAR	ENST00000452476.5	c.1091A>G	p.Lys364Arg	missense_variant	10/10	1		ENSP00000397367.1
LYAR	ENST00000502917.1	n.489A>G		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 08, 2023

The c.1091A>G (p.K364R) alteration is located in exon 10 (coding exon 8) of the LYAR gene. This alteration results from a A to G substitution at nucleotide position 1091, causing the lysine (K) at amino acid position 364 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	17
DANN	Uncertain	1.0
Eigen	Benign	-0.090
Eigen_PC	Benign	0.072
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.041
Sift	Benign	0.19	T;T
Sift4G	Benign	0.27	T;T
Vest4		0.12
MutPred		0.22		Loss of methylation at K364 (P = 0.0111);Loss of methylation at K364 (P = 0.0111);
MVP		0.42
MPC		0.048
ClinPred		0.76	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1718779043; hg19: chr4-4269665;