Genetic Variant NM_015364.5:c.469C>T (chr8-74029040-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_015364.5(LY96):c.469C>T(p.Pro157Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0158 in 1,601,498 control chromosomes in the GnomAD database, including 244 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P157L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.013 ( 21 hom., cov: 32)

Exomes 𝑓: 0.016 ( 223 hom. )

Consequence

LY96
NM_015364.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.200

Publications

18 publications found

Variant links:

Genes affected

LY96 (HGNC:17156): (lymphocyte antigen 96) This gene encodes a protein which associates with toll-like receptor 4 on the cell surface and confers responsiveness to lipopolysaccyaride (LPS), thus providing a link between the receptor and LPS signaling. Studies of the mouse ortholog suggest that this gene may be involved in endotoxin neutralization. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Sep 2010]

LY96 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0031943023).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0126 (1918/152102) while in subpopulation NFE AF = 0.0178 (1213/68010). AF 95% confidence interval is 0.017. There are 21 homozygotes in GnomAd4. There are 923 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LY96	NM_015364.5 link	c.469C>T	p.Pro157Ser	missense_variant	Exon 5 of 5	ENST00000284818.7	NP_056179.4	Q9Y6Y9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LY96	ENST00000284818.7 link	c.469C>T	p.Pro157Ser	missense_variant	Exon 5 of 5	1	NM_015364.5	ENSP00000284818.2		Q9Y6Y9-1
LY96	ENST00000518893.1 link	c.379C>T	p.Pro127Ser	missense_variant	Exon 4 of 4	3		ENSP00000430533.1		Q9Y6Y9-2

Frequencies

GnomAD3 genomes

AF:

0.0126

AC:

1919

AN:

151984

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00312

Gnomad AMI

AF:

0.0571

Gnomad AMR

AF:

0.0153

Gnomad ASJ

AF:

0.00836

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00686

Gnomad FIN

AF:

0.0188

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0178

Gnomad OTH

AF:

0.0139

GnomAD2 exomes

AF:

0.0129

AC:

3231

AN:

250124

AF XY:

0.0133

show subpopulations

Gnomad AFR exome

AF:

0.00334

Gnomad AMR exome

AF:

0.0129

Gnomad ASJ exome

AF:

0.00786

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0198

Gnomad NFE exome

AF:

0.0168

Gnomad OTH exome

AF:

0.0195

GnomAD4 exome

AF:

0.0161

AC:

23381

AN:

1449396

Hom.:

223

Cov.:

AF XY:

0.0160

AC XY:

11518

AN XY:

721756

show subpopulations

African (AFR)

AF:

0.00274

AC:

AN:

33252

American (AMR)

AF:

0.0136

AC:

609

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.00783

AC:

204

AN:

26062

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39588

South Asian (SAS)

AF:

0.00761

AC:

653

AN:

85766

European-Finnish (FIN)

AF:

0.0203

AC:

1072

AN:

52820

Middle Eastern (MID)

AF:

0.00999

AC:

AN:

5504

European-Non Finnish (NFE)

AF:

0.0180

AC:

19786

AN:

1101742

Other (OTH)

AF:

0.0152

AC:

910

AN:

59956

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

988

1976

2965

3953

4941

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

740

1480

2220

2960

3700

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0126

AC:

1918

AN:

152102

Hom.:

Cov.:

AF XY:

0.0124

AC XY:

923

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.00311

AC:

129

AN:

41468

American (AMR)

AF:

0.0153

AC:

233

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00836

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00666

AC:

AN:

4804

European-Finnish (FIN)

AF:

0.0188

AC:

199

AN:

10576

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0178

AC:

1213

AN:

68010

Other (OTH)

AF:

0.0137

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

187

280

374

467

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0147

Hom.:

Bravo

AF:

0.0125

TwinsUK

AF:

0.0191

AC:

ALSPAC

AF:

0.0148

AC:

ESP6500AA

AF:

0.00295

AC:

ESP6500EA

AF:

0.0198

AC:

170

ExAC

AF:

0.0128

AC:

1551

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.0172

EpiControl

AF:

0.0183

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.67

CADD

Benign

8.0

(source)

DANN

Benign

0.66

DEOGEN2

Benign

0.32

T;.

Eigen

Benign

-0.79

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.018

LIST_S2

Benign

0.56

T;T

MetaRNN

Benign

0.0032

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.94

L;.

PhyloP100

0.20

PrimateAI

Benign

0.27

PROVEAN

Uncertain

-2.5

N;D

REVEL

Benign

0.057

Sift

Benign

0.17

T;T

Sift4G

Benign

0.24

T;T

Polyphen

0.021

B;.

Vest4

0.058

MPC

0.11

ClinPred

0.0051

GERP RS

3.3

Varity_R

0.22

gMVP

0.73

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over