chr3-87264299-C-A

Position:

• chr3-87264299-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000306.4(POU1F1):​c.428G>T​(p.Arg143Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,457,598 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: POU1F1 NM_000306.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.23

Genes affected

POU1F1 (HGNC:9210): (POU class 1 homeobox 1) This gene encodes a member of the POU family of transcription factors that regulate mammalian development. The protein regulates expression of several genes involved in pituitary development and hormone expression. Mutations in this genes result in combined pituitary hormone deficiency. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POU1F1	NM_000306.4	c.428G>T	p.Arg143Leu	missense_variant	3/6	ENST00000350375.7	NP_000297.1
POU1F1	NM_001122757.3	c.506G>T	p.Arg169Leu	missense_variant	3/6		NP_001116229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POU1F1	ENST00000350375.7	c.428G>T	p.Arg143Leu	missense_variant	3/6	1	NM_000306.4	ENSP00000263781	P4
POU1F1	ENST00000344265.8	c.506G>T	p.Arg169Leu	missense_variant	3/6	5		ENSP00000342931	A1
POU1F1	ENST00000560656.1	c.428G>T	p.Arg143Leu	missense_variant	3/4	5		ENSP00000452610
POU1F1	ENST00000561167.5	c.215-2064G>T		intron_variant		5		ENSP00000454072

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250860 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135616

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1457598 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 2 AN XY: 725344

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;.;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Pathogenic	2.9	M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-6.3	D;D;D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.97
MutPred		0.93		Loss of MoRF binding (P = 0.0382);.;Loss of MoRF binding (P = 0.0382);
MVP		0.97
MPC		0.37
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.97
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs104893759; hg19: chr3-87313449;