12-7795089-C-A

Variant names:

• chr12-7795089-C-A
• rs778880176
• NM_024865.4:c.912C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_024865.4(NANOG):​c.912C>A​(p.Asp304Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D304D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 29)
  • Exomes 𝑓: 0.0000027 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NANOG NM_024865.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.829
• Publications: 0 publications found

Genes affected

NANOG (HGNC:20857): (Nanog homeobox) The protein encoded by this gene is a DNA binding homeobox transcription factor involved in embryonic stem (ES) cell proliferation, renewal, and pluripotency. The encoded protein can block ES cell differentiation and can also autorepress its own expression in differentiating cells. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2015]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.095950454).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024865.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NANOG	NM_024865.4	MANE Select	c.912C>A	p.Asp304Glu	missense	Exon 4 of 4	NP_079141.2	Q9H9S0-1
	NANOG	NM_001297698.2		c.864C>A	p.Asp288Glu	missense	Exon 4 of 4	NP_001284627.1	Q9H9S0-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NANOG	ENST00000229307.9	TSL:1 MANE Select	c.912C>A	p.Asp304Glu	missense	Exon 4 of 4	ENSP00000229307.4	Q9H9S0-1
	NANOG	ENST00000526286.1	TSL:1	c.864C>A	p.Asp288Glu	missense	Exon 4 of 4	ENSP00000435288.1	Q9H9S0-2
	NANOG	ENST00000933164.1		c.912C>A	p.Asp304Glu	missense	Exon 5 of 5	ENSP00000603223.1

Frequencies

GnomAD3 genomes AF: 0.00000668 AC: 1 AN: 149760 Hom.: 0 Cov.: 29

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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000652 AC: 1 AN: 153480 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000129

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000271 AC: 3 AN: 1105184 Hom.: 0 Cov.: 15 AF XY: 0.00000176 AC XY: 1 AN XY: 566758

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26274

American (AMR) AF: 0.00 AC: 0 AN: 44264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24012

East Asian (EAS) AF: 0.00 AC: 0 AN: 38328

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79394

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37924

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3480

European-Non Finnish (NFE) AF: 0.00000249 AC: 2 AN: 802418

Other (OTH) AF: 0.00 AC: 0 AN: 49090

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000668 AC: 1 AN: 149760 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 73172

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 40102

American (AMR) AF: 0.00 AC: 0 AN: 15076

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4802

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10468

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67388

Other (OTH) AF: 0.00 AC: 0 AN: 2046

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	0.0061	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	10
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.51	D
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.096	T
MetaSVM	Uncertain	0.046	D
MutationAssessor	Benign	1.4	L
PhyloP100		-0.83
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.31
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.013	D
Polyphen		0.98	D
Vest4		0.067
MutPred		0.18		Gain of disorder (P = 0.1544)
MVP		0.70
MPC		1.4
ClinPred		0.51	D
GERP RS		0.015
Varity_R		0.076
gMVP		0.089
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs778880176; hg19: chr12-7947685;