19-50359817-C-T

Variant names:

• chr19-50359817-C-T
• rs115708794
• NM_004851.3:c.714G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004851.3(NAPSA):​c.714G>A​(p.Ser238Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0013 in 1,614,192 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0071 (13 hom., cov: 32)
  • Exomes 𝑓: 0.00069 (10 hom.)
• Consequence: NAPSA NM_004851.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -8.63
• Publications: 1 publications found

Genes affected

NAPSA (HGNC:13395): (napsin A aspartic peptidase) This gene encodes a member of the peptidase A1 family of aspartic proteases. The encoded preproprotein is proteolytically processed to generate an activation peptide and the mature protease. The activation peptides of aspartic proteinases function as inhibitors of the protease active site. These peptide segments, or pro-parts, are deemed important for correct folding, targeting, and control of the activation of aspartic proteinase zymogens. The encoded protease may play a role in the proteolytic processing of pulmonary surfactant protein B in the lung and may function in protein catabolism in the renal proximal tubules. This gene has been described as a marker for lung adenocarcinoma and renal cell carcinoma. [provided by RefSeq, Feb 2016]

NR1H2 (HGNC:7965): (nuclear receptor subfamily 1 group H member 2) The liver X receptors, LXRA (NR1H3; MIM 602423) and LXRB, form a subfamily of the nuclear receptor superfamily and are key regulators of macrophage function, controlling transcriptional programs involved in lipid homeostasis and inflammation. The inducible LXRA is highly expressed in liver, adrenal gland, intestine, adipose tissue, macrophages, lung, and kidney, whereas LXRB is ubiquitously expressed. Ligand-activated LXRs form obligate heterodimers with retinoid X receptors (RXRs; see MIM 180245) and regulate expression of target genes containing LXR response elements (summary by Korf et al., 2009 [PubMed 19436111]).[supplied by OMIM, Jan 2010]

LOC105372437 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 19-50359817-C-T is Benign according to our data. Variant chr19-50359817-C-T is described in ClinVar as Benign. ClinVar VariationId is 716244.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-8.63 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0071 (1081/152316) while in subpopulation AFR AF = 0.0248 (1032/41568). AF 95% confidence interval is 0.0236. There are 13 homozygotes in GnomAd4. There are 521 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004851.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NAPSA	NM_004851.3	MANE Select	c.714G>A	p.Ser238Ser	synonymous	Exon 6 of 9	NP_004842.1	O96009
	NAPSA	NM_001436336.1		c.714G>A	p.Ser238Ser	synonymous	Exon 7 of 10	NP_001423265.1
	NAPSA	NM_001436337.1		c.714G>A	p.Ser238Ser	synonymous	Exon 7 of 8	NP_001423266.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NAPSA	ENST00000253719.7	TSL:1 MANE Select	c.714G>A	p.Ser238Ser	synonymous	Exon 6 of 9	ENSP00000253719.1	O96009
	NAPSA	ENST00000852689.1		c.726G>A	p.Ser242Ser	synonymous	Exon 6 of 9	ENSP00000522748.1
	NAPSA	ENST00000852687.1		c.708G>A	p.Ser236Ser	synonymous	Exon 6 of 9	ENSP00000522746.1

Frequencies

GnomAD3 genomes AF: 0.00710 AC: 1080 AN: 152198 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.0249

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00181 AC: 455 AN: 251394 AF XY: 0.00128

Gnomad AFR exome AF: 0.0251

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000694 AC: 1015 AN: 1461876 Hom.: 10 Cov.: 33 AF XY: 0.000579 AC XY: 421 AN XY: 727242

African (AFR) AF: 0.0240 AC: 805 AN: 33480

American (AMR) AF: 0.00110 AC: 49 AN: 44724

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

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.0000558 AC: 62 AN: 1112002

Other (OTH) AF: 0.00142 AC: 86 AN: 60392

GnomAD4 genome AF: 0.00710 AC: 1081 AN: 152316 Hom.: 13 Cov.: 32 AF XY: 0.00700 AC XY: 521 AN XY: 74476

African (AFR) AF: 0.0248 AC: 1032 AN: 41568

American (AMR) AF: 0.00229 AC: 35 AN: 15294

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68036

Other (OTH) AF: 0.00378 AC: 8 AN: 2116

Alfa AF: 0.00273 Hom.: 5

Bravo AF: 0.00776

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	1.7
DANN	Benign	0.86
PhyloP100		-8.6
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs115708794; hg19: chr19-50863074;