chr6-31592893-C-T

Variant names:

• chr6-31592893-C-T
• rs11575837
• NM_147130.3:c.-172G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 1P and 3B. PP5 BP4 BS1_Supporting BS2_Supporting

The NM_147130.3(NCR3):​c.-172G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0216 in 680,664 control chromosomes in the GnomAD database, including 294 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: 𝑓 0.023 (75 hom., cov: 31)
  • Exomes 𝑓: 0.021 (219 hom.)
• Consequence: NCR3 NM_147130.3 5_prime_UTR
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -2.02

Genes affected

NCR3 (HGNC:19077): (natural cytotoxicity triggering receptor 3) The protein encoded by this gene is a natural cytotoxicity receptor (NCR) that may aid NK cells in the lysis of tumor cells. The encoded protein interacts with CD3-zeta (CD247), a T-cell receptor. A single nucleotide polymorphism in the 5' untranslated region of this gene has been associated with mild malaria suceptibility. Three transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, May 2010]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PP5: Variant 6-31592893-C-T is Pathogenic according to our data. Variant chr6-31592893-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 1803723.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87). . Strength limited to SUPPORTING due to the PP5.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0233 (3539/152184) while in subpopulation AMR AF = 0.039 (595/15262). AF 95% confidence interval is 0.0364. There are 75 homozygotes in GnomAd4. There are 1577 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position FAILED quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 75 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NCR3	NM_147130.3	c.-172G>A		5_prime_UTR_variant	Exon 1 of 4	ENST00000340027.10	NP_667341.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NCR3	ENST00000340027.10	c.-172G>A		5_prime_UTR_variant	Exon 1 of 4	1	NM_147130.3	ENSP00000342156.5

Frequencies

GnomAD3 genomes AF: 0.0233 AC: 3540 AN: 152066 Hom.: 75 Cov.: 31

Gnomad AFR AF: 0.0244

Gnomad AMI AF: 0.00330

Gnomad AMR AF: 0.0390

Gnomad ASJ AF: 0.0979

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0217

Gnomad OTH AF: 0.0398

GnomAD4 exome AF: 0.0212 AC: 11182 AN: 528480 Hom.: 219 Cov.: 6 AF XY: 0.0200 AC XY: 5599 AN XY: 280500

Gnomad4 AFR exome AF: 0.0254 AC: 392 AN: 15416

Gnomad4 AMR exome AF: 0.0401 AC: 1284 AN: 32018

Gnomad4 ASJ exome AF: 0.0935 AC: 1579 AN: 16890

Gnomad4 EAS exome AF: 0.000126 AC: 4 AN: 31728

Gnomad4 SAS exome AF: 0.00194 AC: 107 AN: 55294

Gnomad4 FIN exome AF: 0.00191 AC: 65 AN: 33976

Gnomad4 NFE exome AF: 0.0219 AC: 6806 AN: 310550

Gnomad4 Remaining exome AF: 0.0292 AC: 854 AN: 29230

GnomAD4 genome AF: 0.0233 AC: 3539 AN: 152184 Hom.: 75 Cov.: 31 AF XY: 0.0212 AC XY: 1577 AN XY: 74390

Gnomad4 AFR AF: 0.0244 AC: 0.0243521 AN: 0.0243521

Gnomad4 AMR AF: 0.0390 AC: 0.0389857 AN: 0.0389857

Gnomad4 ASJ AF: 0.0979 AC: 0.0979263 AN: 0.0979263

Gnomad4 EAS AF: 0.000193 AC: 0.000192604 AN: 0.000192604

Gnomad4 SAS AF: 0.00166 AC: 0.00165631 AN: 0.00165631

Gnomad4 FIN AF: 0.00132 AC: 0.001321 AN: 0.001321

Gnomad4 NFE AF: 0.0217 AC: 0.0217206 AN: 0.0217206

Gnomad4 OTH AF: 0.0393 AC: 0.0393365 AN: 0.0393365

Alfa AF: 0.0229 Hom.: 87

Bravo AF: 0.0273

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Malaria, severe, susceptibility to Pathogenic:1

Dec 06, 2022

Center for Global Health, University of New Mexico Health Sciences Center, University of New Mexico

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

CC is wild type in the Luo (Kenya) population, TT is homozygous mutant. TT increases susceptibility to longitudinal (over 36 months) falciparum malaria episodes in children less than 48 months of age. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.71
DANN	Benign	0.76
Mutation Taster		=300/0	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

Publications

LitVar

Other links and lift over

dbSNP: rs11575837; hg19: chr6-31560670;