rs751499789

Variant names:

• chr7-39207462-A-C
• rs751499789
• NM_001370959.1:c.440A>C

Your query was ambiguous. Multiple possible variants found:

• chr7-39207462-A-C
• chr7-39207462-A-G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001370959.1(POU6F2):​c.440A>C​(p.Asn147Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N147S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: POU6F2 NM_001370959.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.84
• Publications: 0 publications found

Genes affected

POU6F2 (HGNC:21694): (POU class 6 homeobox 2) This gene encodes a member of the POU protein family characterized by the presence of a bipartite DNA binding domain, consisting of a POU-specific domain and a homeodomain, separated by a variable polylinker. The DNA binding domain may bind to DNA as monomers or as homo- and/or heterodimers, in a sequence-specific manner. The POU family members are transcriptional regulators, many of which are known to control cell type-specific differentiation pathways. This gene is a tumor suppressor involved in Wilms tumor (WT) predisposition. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene.[provided by RefSeq, Oct 2009]

POU6F2 Gene-Disease associations (from GenCC):

• Wilms tumor 5

  Inheritance: Unknown Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27560282).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001370959.1. 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
	POU6F2	NM_001370959.1	MANE Select	c.440A>C	p.Asn147Thr	missense	Exon 4 of 10	NP_001357888.1	A0A6E1XZL4
	POU6F2	NM_007252.4		c.353A>C	p.Asn118Thr	missense	Exon 5 of 11	NP_009183.3	P78424-1
	POU6F2	NM_001166018.2		c.353A>C	p.Asn118Thr	missense	Exon 5 of 11	NP_001159490.1	P78424-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POU6F2	ENST00000518318.7	TSL:1 MANE Select	c.440A>C	p.Asn147Thr	missense	Exon 4 of 10	ENSP00000430514.3	A0A6E1XZL4
	POU6F2	ENST00000403058.6	TSL:5	c.353A>C	p.Asn118Thr	missense	Exon 5 of 11	ENSP00000384004.1	P78424-1
	POU6F2	ENST00000451021.5	TSL:4	n.492A>C		non_coding_transcript_exon	Exon 4 of 4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000439 AC: 11 AN: 250426 AF XY: 0.00000739

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.0000531

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.84e-7 AC: 1 AN: 1461636 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727102

⚠️ 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: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53354

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111846

Other (OTH) AF: 0.00 AC: 0 AN: 60372

⚠️ 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 Cov.: 33

ExAC AF: 0.000140 AC: 17

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.065	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.088	T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	0.46	N
PhyloP100		5.8
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.30
Sift	Uncertain	0.0040	D
Sift4G	Benign	1.0	T
Polyphen		0.78	P
Vest4		0.72
MutPred		0.18		Gain of glycosylation at N118 (P = 0.0199)
MVP		0.91
MPC		0.38
ClinPred		0.13	T
GERP RS		5.0
Varity_R		0.15
gMVP		0.30
Mutation Taster		=83/17	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: rs751499789; hg19: chr7-39247061;