chr19-54939681-C-G

Variant names:

• chr19-54939681-C-G
• rs104895557
• NM_001127255.2:c.1138G>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_001127255.2(NLRP7):​c.1138G>C​(p.Gly380Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000295 in 1,613,190 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00030 (11 hom.)
• Consequence: NLRP7 NM_001127255.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 0.741
• Publications: 3 publications found

Genes affected

NLRP7 (HGNC:22947): (NLR family pyrin domain containing 7) This gene encodes a member of the NACHT, leucine rich repeat, and PYD containing (NLRP) protein family. It has an N-terminal pyrin domain, followed by a NACHT domain, a NACHT-associated domain (NAD), and a C-terminal leucine-rich repeat (LRR) region. NLRP proteins are implicated in the activation of proinflammatory caspases through multiprotein complexes called inflammasomes. This gene may act as a feedback regulator of caspase-1-dependent interleukin 1-beta secretion. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

NLRP7 Gene-Disease associations (from GenCC):

• hydatidiform mole, recurrent, 1

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• complete hydatidiform mole

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010307968).
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.000304 (444/1460992) while in subpopulation SAS AF = 0.00458 (395/86216). AF 95% confidence interval is 0.00421. There are 11 homozygotes in GnomAdExome4. There are 319 alleles in the male GnomAdExome4 subpopulation. Median coverage is 36. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 11 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001127255.2. 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
	NLRP7	NM_001127255.2	MANE Select	c.1138G>C	p.Gly380Arg	missense	Exon 4 of 11	NP_001120727.1
	NLRP7	NM_001405531.1		c.1138G>C	p.Gly380Arg	missense	Exon 6 of 13	NP_001392460.1
	NLRP7	NM_139176.4		c.1138G>C	p.Gly380Arg	missense	Exon 4 of 11	NP_631915.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLRP7	ENST00000592784.6	TSL:1 MANE Select	c.1138G>C	p.Gly380Arg	missense	Exon 4 of 11	ENSP00000468706.1
	NLRP7	ENST00000588756.5	TSL:1	c.1138G>C	p.Gly380Arg	missense	Exon 6 of 13	ENSP00000467123.1
	NLRP7	ENST00000340844.6	TSL:1	c.1138G>C	p.Gly380Arg	missense	Exon 4 of 10	ENSP00000339491.2

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152080 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00456

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000666 AC: 166 AN: 249364 AF XY: 0.000917

Gnomad AFR exome AF: 0.0000635

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.000304 AC: 444 AN: 1460992 Hom.: 11 Cov.: 36 AF XY: 0.000439 AC XY: 319 AN XY: 726820

African (AFR) AF: 0.000149 AC: 5 AN: 33450

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00458 AC: 395 AN: 86216

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53242

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5212

European-Non Finnish (NFE) AF: 0.0000252 AC: 28 AN: 1111994

Other (OTH) AF: 0.000232 AC: 14 AN: 60322

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152198 Hom.: 0 Cov.: 32 AF XY: 0.000323 AC XY: 24 AN XY: 74402

African (AFR) AF: 0.000193 AC: 8 AN: 41546

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5144

South Asian (SAS) AF: 0.00456 AC: 22 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.0000855 Hom.: 0

Bravo AF: 0.0000680

ExAC AF: 0.000758 AC: 92

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Hydatidiform mole, recurrent, 1 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.040	N
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.48	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		0.74
PrimateAI	Benign	0.28	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Benign	0.23
Sift	Benign	0.030	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.18
MVP		0.47
MPC		0.96
ClinPred		0.18	T
GERP RS		1.9
Varity_R		0.17
gMVP		0.57
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs104895557; hg19: chr19-55451049;