6-125855163-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_181782.5(NCOA7):c.194C>G(p.Thr65Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,460,972 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: 0.0000068 (0 hom.)
• Consequence: NCOA7 NM_181782.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.94

Genes affected

NCOA7 (HGNC:21081): (nuclear receptor coactivator 7) Enables nuclear receptor binding activity and nuclear receptor coactivator activity. Involved in positive regulation of transcription by RNA polymerase II. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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=0.064491004).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NCOA7	NM_181782.5	c.194C>G	p.Thr65Ser	missense_variant	3/16	ENST00000392477.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NCOA7	ENST00000392477.7	c.194C>G	p.Thr65Ser	missense_variant	3/16	1	NM_181782.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000360 AC: 9 AN: 250164 Hom.: 0 AF XY: 0.0000517 AC XY: 7 AN XY: 135322

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000326

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1460972 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 726834

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000757

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000994

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000151

ExAC AF: 0.0000247 AC: 3

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

Sep 29, 2023

The c.194C>G (p.T65S) alteration is located in exon 5 (coding exon 2) of the NCOA7 gene. This alteration results from a C to G substitution at nucleotide position 194, causing the threonine (T) at amino acid position 65 to be replaced by a serine (S). 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	0.091
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	15
Dann	Benign	0.97
DEOGEN2	Benign	0.013	T;T;.;T;.;T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.48	N
M_CAP	Benign	0.0096	T
MetaRNN	Benign	0.064	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L;L;.;.;.;.
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.63	N;N;D;N;D;N
REVEL	Benign	0.052
Sift	Benign	0.086	T;T;T;T;T;T
Sift4G	Benign	0.52	T;T;T;T;T;T
Polyphen		0.0040	B;B;.;.;.;.
Vest4		0.24
MutPred		0.10		Loss of methylation at K70 (P = 0.1144);Loss of methylation at K70 (P = 0.1144);Loss of methylation at K70 (P = 0.1144);Loss of methylation at K70 (P = 0.1144);Loss of methylation at K70 (P = 0.1144);Loss of methylation at K70 (P = 0.1144);
MVP		0.21
MPC		0.10
ClinPred		0.050	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.077
gMVP		0.19

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

Other links and lift over

dbSNP: rs777525135; hg19: chr6-126176309;