Variant chr19-3201538-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_020170.4(NCLN):c.712G>A(p.Ala238Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000142 in 1,407,916 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NCLN
NM_020170.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.36

Variant links:

Genes affected

NCLN (HGNC:26923): (nicalin) Enables ribosome binding activity. Involved in protein stabilization; regulation of protein complex stability; and regulation of protein-containing complex assembly. Located in endoplasmic reticulum membrane. Part of protein-containing complex. [provided by Alliance of Genome Resources, Apr 2022]

NCLN links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.912

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NCLN	NM_020170.4 linkuse as main transcript	c.712G>A	p.Ala238Thr	missense_variant	6/15	ENST00000246117.9	NP_064555.2	Q969V3-1
NCLN	NM_001321463.2 linkuse as main transcript	c.712G>A	p.Ala238Thr	missense_variant	6/15		NP_001308392.1	Q969V3-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
NCLN	ENST00000246117.9 linkuse as main transcript	c.712G>A	p.Ala238Thr	missense_variant	6/15	1	NM_020170.4	ENSP00000246117.3	Q969V3-1
NCLN	ENST00000587740.5 linkuse as main transcript	n.73G>A		non_coding_transcript_exon_variant	2/12	1		ENSP00000466300.1	A0A0C4DGP7
NCLN	ENST00000590671.5 linkuse as main transcript	c.490G>A	p.Ala164Thr	missense_variant	6/15	2		ENSP00000466678.1	K7EMW4
NCLN	ENST00000588428.5 linkuse as main transcript	c.376G>A	p.Ala126Thr	missense_variant	4/9	5		ENSP00000467011.1	K7ENM2

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

152064

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000142

AC:

AN:

1407916

Hom.:

Cov.:

AF XY:

0.00000143

AC XY:

AN XY:

697248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000183

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

152064

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74280

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 07, 2023

The c.712G>A (p.A238T) alteration is located in exon 6 (coding exon 6) of the NCLN gene. This alteration results from a G to A substitution at nucleotide position 712, causing the alanine (A) at amino acid position 238 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.34

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.18

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

.;T;.

Eigen

Uncertain

0.40

Eigen_PC

Benign

0.22

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.97

D;D;D

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.91

D;D;D

MetaSVM

Uncertain

-0.16

MutationAssessor

Pathogenic

3.1

.;M;.

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-3.1

.;D;.

REVEL

Uncertain

0.51

Sift

Uncertain

0.0080

.;D;.

Sift4G

Uncertain

0.021

D;D;D

Polyphen

1.0

.;D;.

Vest4

0.99

MutPred

0.76

.;Gain of relative solvent accessibility (P = 0.0479);.;

MVP

0.80

MPC

1.3

ClinPred

0.95

GERP RS

3.6

RBP_binding_hub_radar

1.0

RBP_regulation_power_radar

2.7

Varity_R

0.22

gMVP

0.90

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over