chr19-56003953-A-C

Position:

chr19-56003953-A-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting

The NM_153447.4(NLRP5):c.300A>C(p.Glu100Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000177 in 1,614,044 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 0.00023 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

NLRP5
NM_153447.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -0.842

Variant links:

Genes affected

NLRP5 (HGNC:21269): (NLR family pyrin domain containing 5) The protein encoded by this gene belongs to the NALP protein family. Members of the NALP protein family typically contain a NACHT domain, a NACHT-associated domain (NAD), a C-terminal leucine-rich repeat (LRR) region, and an N-terminal pyrin domain (PYD). Expression of this gene is restricted to the oocyte. A mouse gene that encodes a maternal oocyte protein, similar to this encoded protein, is required for normal early embryogenesis. [provided by RefSeq, Jul 2008]

NLRP5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.11035681).

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00023 (35/152336) while in subpopulation AMR AF= 0.000588 (9/15296). AF 95% confidence interval is 0.000307. There are 0 homozygotes in gnomad4. There are 14 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NLRP5	NM_153447.4 linkuse as main transcript	c.300A>C	p.Glu100Asp	missense_variant	2/15	ENST00000390649.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NLRP5	ENST00000390649.8 linkuse as main transcript	c.300A>C	p.Glu100Asp	missense_variant	2/15	1	NM_153447.4	P1
NLRP5	ENST00000597673.1 linkuse as main transcript	c.219A>C	p.Glu73Asp	missense_variant, NMD_transcript_variant	1/5	5

Frequencies

GnomAD3 genomes

AF:

0.000230

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000181

AC:

AN:

249252

Hom.:

AF XY:

0.000163

AC XY:

AN XY:

135232

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000186

Gnomad OTH exome

AF:

0.000496

GnomAD4 exome

AF:

0.000172

AC:

251

AN:

1461708

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

127

AN XY:

727136

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.000671

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:

0.000161

Gnomad4 OTH exome

AF:

0.000447

GnomAD4 genome

AF:

0.000230

AC:

AN:

152336

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74504

show subpopulations

Gnomad4 AFR

AF:

0.000192

Gnomad4 AMR

AF:

0.000588

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000165

Hom.:

Bravo

AF:

0.000268

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000359

AC:

ExAC

AF:

0.000132

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 14, 2021

The c.300A>C (p.E100D) alteration is located in exon 2 (coding exon 2) of the NLRP5 gene. This alteration results from a A to C substitution at nucleotide position 300, causing the glutamic acid (E) at amino acid position 100 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

May 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.58

CADD

Benign

7.5

DANN

Uncertain

0.99

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.97

FATHMM_MKL

Benign

0.0064

LIST_S2

Benign

0.40

T;T

M_CAP

Benign

0.0068

MetaRNN

Benign

0.11

T;T

MetaSVM

Benign

-0.80

MutationTaster

Benign

1.0

PrimateAI

Benign

0.31

Sift4G

Uncertain

0.041

D;D

Polyphen

1.0

.;D

Vest4

0.21

MutPred

0.65

Gain of catalytic residue at E100 (P = 0.0513);Gain of catalytic residue at E100 (P = 0.0513);

MVP

0.66

MPC

0.17

ClinPred

0.097

GERP RS

-3.2

Varity_R

0.12

gMVP

0.13

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over