Variant chr7-45081858-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001146334.2(NACAD):c.4082G>A(p.Arg1361Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000291 in 1,545,542 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1361P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

NACAD
NM_001146334.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.75

Variant links:

Genes affected

NACAD (HGNC:22196): (NAC alpha domain containing) Predicted to enable unfolded protein binding activity. Predicted to be involved in protein targeting to membrane. Predicted to be located in nucleus. Predicted to be part of nascent polypeptide-associated complex. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

NACAD links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.12485772).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NACAD	NM_001146334.2 linkuse as main transcript	c.4082G>A	p.Arg1361Gln	missense_variant	3/8	ENST00000490531.3
NACAD	XM_006715674.4 linkuse as main transcript	c.3443G>A	p.Arg1148Gln	missense_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NACAD	ENST00000490531.3 linkuse as main transcript	c.4082G>A	p.Arg1361Gln	missense_variant	3/8	5	NM_001146334.2	P1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152062

Hom.:

Cov.:

show subpopulations

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:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000265

AC:

AN:

150890

Hom.:

AF XY:

0.0000249

AC XY:

AN XY:

80368

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000405

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000918

Gnomad SAS exome

AF:

0.0000439

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000168

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000294

AC:

AN:

1393480

Hom.:

Cov.:

AF XY:

0.0000320

AC XY:

AN XY:

687522

show subpopulations

Gnomad4 AFR exome

AF:

0.0000317

Gnomad4 AMR exome

AF:

0.0000280

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000280

Gnomad4 SAS exome

AF:

0.0000884

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000250

Gnomad4 OTH exome

AF:

0.0000692

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152062

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74258

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000241

Hom.:

Bravo

AF:

0.0000151

Asia WGS

AF:

0.000289

AC:

AN:

3478

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

May 16, 2023

The c.4082G>A (p.R1361Q) alteration is located in exon 3 (coding exon 3) of the NACAD gene. This alteration results from a G to A substitution at nucleotide position 4082, causing the arginine (R) at amino acid position 1361 to be replaced by a glutamine (Q). 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

0.086

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.74

CADD

Benign

7.7

DANN

Uncertain

0.99

DEOGEN2

Benign

0.020

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.87

FATHMM_MKL

Benign

0.0082

LIST_S2

Benign

0.58

M_CAP

Benign

0.047

MetaRNN

Benign

0.12

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

MutationTaster

Benign

1.0

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.9

REVEL

Benign

0.054

Sift

Uncertain

0.013

Sift4G

Benign

0.24

Polyphen

1.0

Vest4

0.061

MutPred

0.18

Loss of loop (P = 0.0986);

MVP

0.067

MPC

0.0060

ClinPred

0.15

GERP RS

-0.51

Varity_R

0.052

gMVP

0.049

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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