14-74480120-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS1

The NM_006432.5(NPC2):c.*154G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000541 in 1,562,398 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0030 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00028 (3 hom.)
• Consequence: NPC2 NM_006432.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.103

Genes affected

NPC2 (HGNC:14537): (NPC intracellular cholesterol transporter 2) This gene encodes a protein containing a lipid recognition domain. The encoded protein may function in regulating the transport of cholesterol through the late endosomal/lysosomal system. Mutations in this gene have been associated with Niemann-Pick disease, type C2 and frontal lobe atrophy. [provided by RefSeq, Jul 2008]

SYNDIG1L (HGNC:):

MIR4709 (HGNC:41690): (microRNA 4709) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004185885).
• BP6: Variant 14-74480120-C-T is Benign according to our data. Variant chr14-74480120-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1300451.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00295 (449/152174) while in subpopulation AFR AF= 0.01 (416/41510). AF 95% confidence interval is 0.00923. There are 1 homozygotes in gnomad4. There are 205 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPC2	NM_006432.5	c.*154G>A		3_prime_UTR_variant	5/5	ENST00000555619.6
MIR4709	NR_039858.1			downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPC2	ENST00000555619.6	c.*154G>A		3_prime_UTR_variant	5/5	1	NM_006432.5	P4
MIR4709	ENST00000577272.1			downstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.00297 AC: 451 AN: 152056 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00288

GnomAD3 exomes AF: 0.000621 AC: 108 AN: 174000 Hom.: 0 AF XY: 0.000567 AC XY: 53 AN XY: 93546

Gnomad AFR exome AF: 0.00936

Gnomad AMR exome AF: 0.000451

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000674

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000281 AC: 396 AN: 1410224 Hom.: 3 Cov.: 32 AF XY: 0.000258 AC XY: 180 AN XY: 697670

Gnomad4 AFR exome AF: 0.00921

Gnomad4 AMR exome AF: 0.000534

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000124

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000303

Gnomad4 OTH exome AF: 0.000783

GnomAD4 genome AF: 0.00295 AC: 449 AN: 152174 Hom.: 1 Cov.: 32 AF XY: 0.00276 AC XY: 205 AN XY: 74380

Gnomad4 AFR AF: 0.0100

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00285

Alfa AF: 0.00156 Hom.: 0

Bravo AF: 0.00329

ExAC AF: 0.000662 AC: 79

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 18, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	5.1
Dann	Benign	0.56
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.071	N
LIST_S2	Benign	0.35	T
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-0.53	T
MutationTaster	Benign	1.0	N;N;N;N
PROVEAN	Benign	0.0	N
REVEL	Benign	0.031
Sift	Benign	0.38	T
MVP		0.65
ClinPred		0.0045	T
GERP RS		-0.036

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: rs142355730; hg19: chr14-74946823;