4-4274763-C-T

Position:

• chr4-4274763-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000343470.9(LYAR):​c.436G>A​(p.Val146Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000342 in 1,589,710 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00035 (0 hom.)
• Consequence: LYAR ENST00000343470.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0590

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.042229652).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LYAR	NM_017816.3	c.436G>A	p.Val146Ile	missense_variant	7/10	ENST00000343470.9	NP_060286.1
LYAR	NM_001145725.2	c.436G>A	p.Val146Ile	missense_variant	7/10		NP_001139197.1
LYAR	XM_011513505.2	c.436G>A	p.Val146Ile	missense_variant	7/10		XP_011511807.1
LYAR	XM_011513506.4	c.436G>A	p.Val146Ile	missense_variant	6/9		XP_011511808.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LYAR	ENST00000343470.9	c.436G>A	p.Val146Ile	missense_variant	7/10	1	NM_017816.3	ENSP00000345917	P1
LYAR	ENST00000452476.5	c.436G>A	p.Val146Ile	missense_variant	7/10	1		ENSP00000397367	P1

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152082 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000945

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000255 AC: 58 AN: 227522 Hom.: 0 AF XY: 0.000219 AC XY: 27 AN XY: 123232

Gnomad AFR exome AF: 0.000127

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000955

Gnomad NFE exome AF: 0.000503

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000353 AC: 508 AN: 1437628 Hom.: 0 Cov.: 32 AF XY: 0.000313 AC XY: 224 AN XY: 714666

Gnomad4 AFR exome AF: 0.0000317

Gnomad4 AMR exome AF: 0.0000538

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000566

Gnomad4 NFE exome AF: 0.000446

Gnomad4 OTH exome AF: 0.000152

GnomAD4 genome AF: 0.000237 AC: 36 AN: 152082 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15 AN XY: 74292

Gnomad4 AFR AF: 0.0000725

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000945

Gnomad4 NFE AF: 0.000441

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000418 Hom.: 0

Bravo AF: 0.000280

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000247 AC: 30

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000593

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 12, 2021

The c.436G>A (p.V146I) alteration is located in exon 7 (coding exon 5) of the LYAR gene. This alteration results from a G to A substitution at nucleotide position 436, causing the valine (V) at amino acid position 146 to be replaced by an isoleucine (I). 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	0.074
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	15
DANN	Benign	0.93
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.064	N
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.042	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.42	N;N
REVEL	Benign	0.046
Sift	Benign	0.18	T;T
Sift4G	Benign	0.21	T;T
Vest4		0.082
MVP		0.23
MPC		0.052
ClinPred		0.021	T
GERP RS		2.6
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: -9

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs201897727; hg19: chr4-4276490;