2-24665821-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003743.5(NCOA1):c.162T>G(p.Ile54Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,454,178 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 (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: NCOA1 NM_003743.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.857

Genes affected

NCOA1 (HGNC:7668): (nuclear receptor coactivator 1) The protein encoded by this gene acts as a transcriptional coactivator for steroid and nuclear hormone receptors. It is a member of the p160/steroid receptor coactivator (SRC) family and like other family members has histone acetyltransferase activity and contains a nuclear localization signal, as well as bHLH and PAS domains. The product of this gene binds nuclear receptors directly and stimulates the transcriptional activities in a hormone-dependent fashion. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

ACMG classification

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=0.08894825).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NCOA1	NM_003743.5	c.162T>G	p.Ile54Met	missense_variant	6/23	ENST00000348332.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NCOA1	ENST00000348332.8	c.162T>G	p.Ile54Met	missense_variant	6/23	1	NM_003743.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1454178 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 723616

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: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 24, 2023

The c.162T>G (p.I54M) alteration is located in exon 4 (coding exon 2) of the NCOA1 gene. This alteration results from a T to G substitution at nucleotide position 162, causing the isoleucine (I) at amino acid position 54 to be replaced by a methionine (M). 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	0.17
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	14
Dann	Benign	0.95
DEOGEN2	Benign	0.11	T;.;.;T;.
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.20	N
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.089	T;T;T;T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	1.0	L;L;L;L;L
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.61	N;N;N;N;N
REVEL	Benign	0.15
Sift	Benign	0.21	T;T;T;T;T
Sift4G	Benign	0.32	T;T;T;T;T
Polyphen		0.22	B;P;P;B;P
Vest4		0.32
MutPred		0.20		Loss of stability (P = 0.1393);Loss of stability (P = 0.1393);Loss of stability (P = 0.1393);Loss of stability (P = 0.1393);Loss of stability (P = 0.1393);
MVP		0.24
MPC		1.2
ClinPred		0.45	T
GERP RS		0.40
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.18

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-24888690; COSMIC: COSV99946880;