6-31164789-C-T

Variant names:

• chr6-31164789-C-T
• rs758948344
• NM_002701.6:c.895G>A

Variant summary

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

The NM_002701.6(POU5F1):​c.895G>A​(p.Glu299Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,392 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. E299Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: POU5F1 NM_002701.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.15
• Publications: 0 publications found

Genes affected

POU5F1 (HGNC:9221): (POU class 5 homeobox 1) This gene encodes a transcription factor containing a POU homeodomain that plays a key role in embryonic development and stem cell pluripotency. Aberrant expression of this gene in adult tissues is associated with tumorigenesis. This gene can participate in a translocation with the Ewing's sarcoma gene on chromosome 21, which also leads to tumor formation. Alternative splicing, as well as usage of alternative AUG and non-AUG translation initiation codons, results in multiple isoforms. One of the AUG start codons is polymorphic in human populations. Related pseudogenes have been identified on chromosomes 1, 3, 8, 10, and 12. [provided by RefSeq, Oct 2013]

TCF19 (HGNC:11629): (transcription factor 19) This gene encodes a protein that contains a PHD-type zinc finger domain and likely functions as a transcription factor. The encoded protein plays a role proliferation and apoptosis of pancreatic beta cells. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

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=0.2873184).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POU5F1	NM_002701.6	c.895G>A	p.Glu299Lys	missense_variant	Exon 5 of 5	ENST00000259915.13	NP_002692.2
POU5F1	NM_001173531.3	c.385G>A	p.Glu129Lys	missense_variant	Exon 5 of 5		NP_001167002.1
POU5F1	NM_203289.6	c.385G>A	p.Glu129Lys	missense_variant	Exon 4 of 4		NP_976034.4
POU5F1	NM_001285986.2	c.307G>A	p.Glu103Lys	missense_variant	Exon 3 of 3		NP_001272915.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POU5F1	ENST00000259915.13	c.895G>A	p.Glu299Lys	missense_variant	Exon 5 of 5	1	NM_002701.6	ENSP00000259915.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460392 Hom.: 0 Cov.: 96 AF XY: 0.00 AC XY: 0 AN XY: 726428

African (AFR) AF: 0.00 AC: 0 AN: 33440

American (AMR) AF: 0.00 AC: 0 AN: 44504

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86028

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53172

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111352

Other (OTH) AF: 0.00 AC: 0 AN: 60342

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000838 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Uncertain	0.051	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	23
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.30	T;T;T;.;T;T;T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.92	.;.;.;D;.;D;D
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.29	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.098	D
MutationAssessor	Uncertain	2.1	M;.;.;.;.;.;.
PhyloP100		5.1
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.8	N;N;N;.;N;.;.
REVEL	Uncertain	0.34
Sift	Benign	0.092	T;T;T;.;T;.;.
Sift4G	Benign	0.31	T;T;T;T;T;T;T
Polyphen		0.55	P;.;.;.;.;.;.
Vest4		0.19
MutPred		0.34		Gain of ubiquitination at E299 (P = 0.0042);.;.;.;.;.;.;
MVP		0.64
MPC		2.0
ClinPred		0.48	T
GERP RS		5.8
Varity_R		0.14
gMVP		0.79
Mutation Taster		=89/11	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: rs758948344; hg19: chr6-31132566;