13-78601835-G-C

Position:

• chr13-78601835-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_006237.4(POU4F1):​c.840C>G​(p.Ile280Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: POU4F1 NM_006237.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.74

Genes affected

POU4F1 (HGNC:9218): (POU class 4 homeobox 1) This gene encodes a member of the POU-IV class of neural transcription factors. This protein is expressed in a subset of retinal ganglion cells and may be involved in the developing sensory nervous system. This protein may also promote the growth of cervical tumors. A translocation of this gene is associated with some adult acute myeloid leukemias. [provided by RefSeq, Mar 2012]

POU4F1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.917

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POU4F1	NM_006237.4	c.840C>G	p.Ile280Met	missense_variant	2/2	ENST00000377208.7	NP_006228.3
POU4F1	XR_007063683.1	n.1320C>G		non_coding_transcript_exon_variant	1/2
OBI1-AS1	NR_047001.1	n.385-3466G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POU4F1	ENST00000377208.7	c.840C>G	p.Ile280Met	missense_variant	2/2	1	NM_006237.4	ENSP00000366413.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 12, 2024

De novo variant with confirmed parentage in a patient referred for genetic testing at GeneDx; however, the reported clinical features are only partially consistent with the features typically observed in individuals with pathogenic variants in this gene; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	28
DANN	Benign	0.93
DEOGEN2	Uncertain	0.74	D
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	0.56	D
MutationAssessor	Uncertain	2.2	M
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-2.5	D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.99	D
Vest4		0.82
MutPred		0.69		Gain of catalytic residue at V284 (P = 0.0288);
MVP		0.83
ClinPred		0.95	D
GERP RS		2.3
Varity_R		0.54
gMVP		0.78

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: chr13-79175970;