3-87259946-C-T

Variant names:

• chr3-87259946-C-T
• NM_000306.4:c.824G>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000306.4(POU1F1):​c.824G>A​(p.Ser275Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000752 in 1,461,846 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: POU1F1 NM_000306.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.54

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a chain Pituitary-specific positive transcription factor 1 (size 290) in uniprot entity PIT1_HUMAN there are 19 pathogenic changes around while only 8 benign (70%) in NM_000306.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POU1F1	NM_000306.4	c.824G>A	p.Ser275Asn	missense_variant	Exon 6 of 6	ENST00000350375.7	NP_000297.1
POU1F1	NM_001122757.3	c.902G>A	p.Ser301Asn	missense_variant	Exon 6 of 6		NP_001116229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POU1F1	ENST00000350375.7	c.824G>A	p.Ser275Asn	missense_variant	Exon 6 of 6	1	NM_000306.4	ENSP00000263781.2
POU1F1	ENST00000344265.8	c.902G>A	p.Ser301Asn	missense_variant	Exon 6 of 6	5		ENSP00000342931.3
POU1F1	ENST00000561167.5	c.599G>A	p.Ser200Asn	missense_variant	Exon 5 of 5	5		ENSP00000454072.1
POU1F1	ENST00000560656	c.*88G>A		3_prime_UTR_variant	Exon 4 of 4	5		ENSP00000452610.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000752 AC: 11 AN: 1461846 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 727220

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jan 29, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter 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	Uncertain	0.45
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T;.;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.60	D;D;D
MetaSVM	Uncertain	0.68	D
MutationAssessor	Benign	1.4	L;.;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.6	N;N;N
REVEL	Uncertain	0.49
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.010	D;D;.
Polyphen		0.99	D;D;.
Vest4		0.67
MutPred		0.26		Gain of glycosylation at T274 (P = 0.0327);.;.;
MVP		0.79
MPC		0.33
ClinPred		0.98	D
GERP RS		6.1
Varity_R		0.27
gMVP		0.36

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: chr3-87309096;