chr11-7039746-A-T

Variant names:

• chr11-7039746-A-T
• rs76274604
• NM_176822.4:c.322A>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.728
• Publications: 10 publications found

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

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_176822.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRP14	NM_176822.4	MANE Select	c.322A>T	p.Lys108*	stop_gained	Exon 3 of 12	NP_789792.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRP14	ENST00000299481.5	TSL:5 MANE Select	c.322A>T	p.Lys108*	stop_gained	Exon 3 of 12	ENSP00000299481.5

Frequencies

GnomAD3 genomes AF: 0.00516 AC: 785 AN: 152186 Hom.: 19 Cov.: 32

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

GnomAD2 exomes AF: 0.0116 AC: 2908 AN: 251302 AF XY: 0.00867

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 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.: 30 AF XY: 0.00246 AC XY: 1787 AN XY: 727212

African (AFR) AF: 0.000329 AC: 11 AN: 33474

American (AMR) AF: 0.0674 AC: 3013 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0235 AC: 933 AN: 39698

South Asian (SAS) AF: 0.000406 AC: 35 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000180 AC: 20 AN: 1111934

Other (OTH) AF: 0.00280 AC: 169 AN: 60390

GnomAD4 genome AF: 0.00517 AC: 788 AN: 152304 Hom.: 19 Cov.: 32 AF XY: 0.00577 AC XY: 430 AN XY: 74468

African (AFR) AF: 0.000529 AC: 22 AN: 41568

American (AMR) AF: 0.0405 AC: 619 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.0251 AC: 130 AN: 5182

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4818

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68028

Other (OTH) AF: 0.00473 AC: 10 AN: 2114

Alfa AF: 0.00128 Hom.: 2

Bravo AF: 0.00851

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000582 AC: 5

ExAC AF: 0.00846 AC: 1027

Asia WGS AF: 0.0100 AC: 36 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	NLRP14-related disorder (1)
-	-	1	not specified (1)
-	-	1	Spermatogenic Failure (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Benign	-0.079
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.086	N
PhyloP100		0.73
Vest4		0.18
GERP RS		1.3
Mutation Taster		=77/123	polymorphism (auto)

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

Other links and lift over

dbSNP: rs76274604; hg19: chr11-7060977; COSMIC: COSV55065185;