12-7794821-C-A

Variant names:

• chr12-7794821-C-A
• NM_024865.4:c.644C>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_024865.4(NANOG):​c.644C>A​(p.Ser215Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S215A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 25)
• Consequence: NANOG NM_024865.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.09

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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28047428).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NANOG	NM_024865.4	c.644C>A	p.Ser215Tyr	missense_variant	Exon 4 of 4	ENST00000229307.9	NP_079141.2
NANOG	NM_001297698.2	c.596C>A	p.Ser199Tyr	missense_variant	Exon 4 of 4		NP_001284627.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NANOG	ENST00000229307.9	c.644C>A	p.Ser215Tyr	missense_variant	Exon 4 of 4	1	NM_024865.4	ENSP00000229307.4
NANOG	ENST00000526286.1	c.596C>A	p.Ser199Tyr	missense_variant	Exon 4 of 4	1		ENSP00000435288.1
NANOG	ENST00000541267.5	c.*13C>A		downstream_gene_variant		5		ENSP00000444434.1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 25

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 16, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.644C>A (p.S215Y) alteration is located in exon 4 (coding exon 4) of the NANOG gene. This alteration results from a C to A substitution at nucleotide position 644, causing the serine (S) at amino acid position 215 to be replaced by a tyrosine (Y). 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	Uncertain	0.092	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.61	D;.
Eigen	Benign	-0.091
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.067	N
LIST_S2	Benign	0.83	T;T
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.28	T;T
MetaSVM	Uncertain	0.0063	D
MutationAssessor	Uncertain	2.6	M;.
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-2.4	N;D
REVEL	Uncertain	0.35
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.012	D;D
Polyphen		0.98	D;.
Vest4		0.26
MutPred		0.40		Loss of disorder (P = 0.0064);.;
MVP		0.81
MPC		2.1
ClinPred		0.94	D
GERP RS		2.2
Varity_R		0.15
gMVP		0.37

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: chr12-7947417;