Variant 7-45081638-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001146334.2(NACAD):c.4220A>G(p.Lys1407Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000413 in 1,551,418 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

NACAD
NM_001146334.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.976

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.048751026).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NACAD	NM_001146334.2 linkuse as main transcript	c.4220A>G	p.Lys1407Arg	missense_variant	4/8	ENST00000490531.3
NACAD	XM_006715674.4 linkuse as main transcript	c.3581A>G	p.Lys1194Arg	missense_variant	5/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NACAD	ENST00000490531.3 linkuse as main transcript	c.4220A>G	p.Lys1407Arg	missense_variant	4/8	5	NM_001146334.2	P1

Frequencies

GnomAD3 genomes

AF:

0.000210

AC:

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000603

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

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:

0.00144

GnomAD3 exomes

AF:

0.0000450

AC:

AN:

155704

Hom.:

AF XY:

0.0000484

AC XY:

AN XY:

82576

show subpopulations

Gnomad AFR exome

AF:

0.000757

Gnomad AMR exome

AF:

0.0000405

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000229

AC:

AN:

1399174

Hom.:

Cov.:

AF XY:

0.0000159

AC XY:

AN XY:

690112

show subpopulations

Gnomad4 AFR exome

AF:

0.000633

Gnomad4 AMR exome

AF:

0.0000280

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:

0.00000556

Gnomad4 OTH exome

AF:

0.0000862

GnomAD4 genome

AF:

0.000210

AC:

AN:

152244

Hom.:

Cov.:

AF XY:

0.000255

AC XY:

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.000602

Gnomad4 AMR

AF:

0.000262

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:

0.00142

Alfa

AF:

0.000172

Hom.:

Bravo

AF:

0.000268

ExAC

AF:

0.0000760

AC:

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

Feb 17, 2023

The c.4220A>G (p.K1407R) alteration is located in exon 4 (coding exon 4) of the NACAD gene. This alteration results from a A to G substitution at nucleotide position 4220, causing the lysine (K) at amino acid position 1407 to be replaced by an arginine (R). 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

0.13

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.58

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.047

Eigen

Benign

0.17

Eigen_PC

Benign

0.16

FATHMM_MKL

Benign

0.65

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.0083

MetaRNN

Benign

0.049

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

MutationTaster

Benign

0.98

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-2.6

REVEL

Benign

0.094

Sift

Benign

0.043

Sift4G

Benign

0.15

Polyphen

0.96

Vest4

0.19

MVP

0.13

MPC

0.010

ClinPred

0.18

GERP RS

3.4

Varity_R

0.25

gMVP

0.23

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

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