Genetic Variant NM_006540.4:c.4279A>T (chr8-70123898-T-A) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_006540.4(NCOA2):c.4279A>T(p.Met1427Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000089 in 1,460,096 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

NCOA2
NM_006540.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.63

Variant links:

Genes affected

NCOA2 (HGNC:7669): (nuclear receptor coactivator 2) The protein encoded by this gene functions as a transcriptional coactivator for nuclear hormone receptors, including steroid, thyroid, retinoid, and vitamin D receptors. The encoded protein acts as an intermediary factor for the ligand-dependent activity of these nuclear receptors, which regulate their target genes upon binding of cognate response elements. This gene has been found to be involved in translocations that result in fusions with other genes in various cancers, including the lysine acetyltransferase 6A (KAT6A) gene in acute myeloid leukemia, the ETS variant 6 (ETV6) gene in acute lymphoblastic leukemia, and the hes related family bHLH transcription factor with YRPW motif 1 (HEY1) gene in mesenchymal chondrosarcoma. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2016]

NCOA2 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.27289256).

BS2

High AC in GnomAdExome4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NCOA2	NM_006540.4 link	c.4279A>T	p.Met1427Leu	missense_variant	Exon 21 of 23	ENST00000452400.7	NP_006531.1	Q15596

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NCOA2	ENST00000452400.7 link	c.4279A>T	p.Met1427Leu	missense_variant	Exon 21 of 23	1	NM_006540.4	ENSP00000399968.2	Q15596
NCOA2	ENST00000518363.2 link	c.1654A>T	p.Met552Leu	missense_variant	Exon 9 of 11	2		ENSP00000429132.2	H0YBB6
NCOA2	ENST00000518287.6 link	n.*1236A>T		non_coding_transcript_exon_variant	Exon 20 of 21	5		ENSP00000430148.2	E7EWM1
NCOA2	ENST00000518287.6 link	n.*1236A>T		3_prime_UTR_variant	Exon 20 of 21	5		ENSP00000430148.2	E7EWM1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000404

AC:

AN:

247788

Hom.:

AF XY:

0.00000744

AC XY:

AN XY:

134354

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000328

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000890

AC:

AN:

1460096

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

726146

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:

0.000140

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000825

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.45

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.23

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.0068

MetaRNN

Benign

0.27

MetaSVM

Benign

-1.2

MutationAssessor

Benign

1.9

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-1.9

REVEL

Benign

0.12

Sift

Benign

0.077

Sift4G

Benign

0.12

Polyphen

0.78

Vest4

0.42

MutPred

0.20

Gain of glycosylation at S1426 (P = 0.0584);

MVP

0.44

MPC

0.12

ClinPred

0.55

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.25

gMVP

0.54

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over