11-7038729-A-C

Position:

• chr11-7038729-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_176822.4(NLRP14):​c.143A>C​(p.Asn48Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.994 in 1,614,088 control chromosomes in the GnomAD database, including 798,171 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.97 (71622 hom., cov: 31)
  • Exomes 𝑓: 1.0 (726549 hom.)
• Consequence: NLRP14 NM_176822.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0930

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.7445806E-7).
• BP6: Variant 11-7038729-A-C is Benign according to our data. Variant chr11-7038729-A-C is described in ClinVar as [Benign]. Clinvar id is 1234647.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NLRP14	NM_176822.4	c.143A>C	p.Asn48Thr	missense_variant	2/12	ENST00000299481.5	NP_789792.1
NLRP14	XM_011520044.2	c.143A>C	p.Asn48Thr	missense_variant	2/11		XP_011518346.1
NLRP14	XM_047426867.1	c.143A>C	p.Asn48Thr	missense_variant	2/11		XP_047282823.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NLRP14	ENST00000299481.5	c.143A>C	p.Asn48Thr	missense_variant	2/12	5	NM_176822.4	ENSP00000299481	P1

Frequencies

GnomAD3 genomes AF: 0.969 AC: 147404 AN: 152122 Hom.: 71577 Cov.: 31

Gnomad AFR AF: 0.891

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.990

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 1.00

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.980

GnomAD3 exomes AF: 0.991 AC: 249068 AN: 251224 Hom.: 123570 AF XY: 0.994 AC XY: 134947 AN XY: 135798

Gnomad AFR exome AF: 0.882

Gnomad AMR exome AF: 0.995

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.997

GnomAD4 exome AF: 0.997 AC: 1457252 AN: 1461848 Hom.: 726549 Cov.: 50 AF XY: 0.997 AC XY: 725327 AN XY: 727228

Gnomad4 AFR exome AF: 0.889

Gnomad4 AMR exome AF: 0.994

Gnomad4 ASJ exome AF: 1.00

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 1.00

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 1.00

Gnomad4 OTH exome AF: 0.994

GnomAD4 genome AF: 0.969 AC: 147506 AN: 152240 Hom.: 71622 Cov.: 31 AF XY: 0.969 AC XY: 72143 AN XY: 74438

Gnomad4 AFR AF: 0.891

Gnomad4 AMR AF: 0.990

Gnomad4 ASJ AF: 1.00

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 1.00

Gnomad4 FIN AF: 1.00

Gnomad4 NFE AF: 1.00

Gnomad4 OTH AF: 0.980

Alfa AF: 0.993 Hom.: 124196

Bravo AF: 0.964

TwinsUK AF: 1.00 AC: 3708

ALSPAC AF: 0.999 AC: 3852

ESP6500AA AF: 0.894 AC: 3934

ESP6500EA AF: 1.00 AC: 8588

ExAC AF: 0.990 AC: 120144

Asia WGS AF: 0.995 AC: 3459 AN: 3478

EpiCase AF: 1.00

EpiControl AF: 1.00

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	- -

NLRP14-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 24, 2019

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.23
DANN	Benign	0.65
DEOGEN2	Benign	0.0042	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0034	N
LIST_S2	Benign	0.13	T
MetaRNN	Benign	5.7e-7	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-2.6	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.26	T
PROVEAN	Benign	2.2	N
REVEL	Benign	0.067
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.035
MPC		0.018
ClinPred		0.017	T
GERP RS		2.4
Varity_R		0.18
gMVP		0.11

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: rs12801277; hg19: chr11-7059960;