chr11-7039746-A-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_176822.4(NLRP14):c.322A>T(p.Lys108*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00308 in 1,614,102 control chromosomes in the GnomAD database, including 136 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0052 ( 19 hom., cov: 32)

Exomes 𝑓: 0.0029 ( 117 hom. )

Consequence

NLRP14
NM_176822.4 stop_gained

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.728

Variant links:

Genes affected

NLRP14 (HGNC:22939): (NLR family pyrin domain containing 14) 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). This protein may play a regulatory role in the innate immune system as similar family members belong to the signal-induced multiprotein complex, the inflammasome, that activates the pro-inflammatory caspases, caspase-1 and caspase-5. [provided by RefSeq, Jul 2008]

NLRP14 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6

Variant 11-7039746-A-T is Benign according to our data. Variant chr11-7039746-A-T is described in ClinVar as [Benign]. Clinvar id is 235386.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0654 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLRP14	NM_176822.4 link	c.322A>T	p.Lys108*	stop_gained	Exon 3 of 12	ENST00000299481.5	NP_789792.1	Q86W24
NLRP14	XM_011520044.2 link	c.322A>T	p.Lys108*	stop_gained	Exon 3 of 11		XP_011518346.1
NLRP14	XM_047426867.1 link	c.322A>T	p.Lys108*	stop_gained	Exon 3 of 11		XP_047282823.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NLRP14	ENST00000299481.5 link	c.322A>T	p.Lys108*	stop_gained	Exon 3 of 12	5	NM_176822.4	ENSP00000299481.5		Q86W24

Frequencies

GnomAD3 genomes

AF:

0.00516

AC:

785

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000531

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0403

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0252

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00478

GnomAD3 exomes

AF:

0.0116

AC:

2908

AN:

251302

Hom.:

AF XY:

0.00867

AC XY:

1178

AN XY:

135812

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.0715

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0202

Gnomad SAS exome

AF:

0.000359

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00669

GnomAD4 exome

AF:

0.00286

AC:

4181

AN:

1461798

Hom.:

117

Cov.:

AF XY:

0.00246

AC XY:

1787

AN XY:

727212

show subpopulations

Gnomad4 AFR exome

AF:

0.000329

Gnomad4 AMR exome

AF:

0.0674

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0235

Gnomad4 SAS exome

AF:

0.000406

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000180

Gnomad4 OTH exome

AF:

0.00280

GnomAD4 genome

AF:

0.00517

AC:

788

AN:

152304

Hom.:

Cov.:

AF XY:

0.00577

AC XY:

430

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.000529

Gnomad4 AMR

AF:

0.0405

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0251

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.00128

Hom.:

Bravo

AF:

0.00851

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000582

AC:

ExAC

AF:

0.00846

AC:

1027

Asia WGS

AF:

0.0100

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 22, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 20981092, 22344438, 25525159, 16931801, 27535533) -

NLRP14-related disorder

Benign:1

Oct 18, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not specified

Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Spermatogenic Failure

Benign:1

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

The heterozygous c.Lys108Ter variant in NLRP14 has been identified in an individual with azoospermia or severe oligozoospermia (PMID: 16931801), but has also been identified in >7% of Latino chromosomes and 34 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for autosomal recessive spermatogenic failure. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.075

BayesDel_noAF

Pathogenic

0.17

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Benign

-0.079

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.086

Vest4

0.18

GERP RS

1.3

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.21

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.21

Position offset: -32

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