3-87264357-T-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_000306.4(POU1F1):c.370A>C(p.Met124Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,734 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict 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. M124V) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

POU1F1
NM_000306.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.33

Publications

0 publications found

Variant links:

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]

POU1F1 Gene-Disease associations (from GenCC):

pituitary hormone deficiency, combined, 1
Inheritance: AD, AR, SD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
combined pituitary hormone deficiencies, genetic form
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hypothyroidism due to deficient transcription factors involved in pituitary development or function
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
isolated growth hormone deficiency type II
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

POU1F1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 15 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 0.45719 (below the threshold of 3.09). Trascript score misZ: 0.74343 (below the threshold of 3.09). GenCC associations: The gene is linked to pituitary hormone deficiency, combined, 1, isolated growth hormone deficiency type II, combined pituitary hormone deficiencies, genetic form, hypothyroidism due to deficient transcription factors involved in pituitary development or function.

BP4

Computational evidence support a benign effect (MetaRNN=0.20840615).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POU1F1	NM_000306.4 link	c.370A>C	p.Met124Leu	missense_variant	Exon 3 of 6	ENST00000350375.7	NP_000297.1
POU1F1	NM_001122757.3 link	c.448A>C	p.Met150Leu	missense_variant	Exon 3 of 6		NP_001116229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
POU1F1	ENST00000350375.7 link	c.370A>C	p.Met124Leu	missense_variant	Exon 3 of 6	1	NM_000306.4	ENSP00000263781.2
POU1F1	ENST00000344265.8 link	c.448A>C	p.Met150Leu	missense_variant	Exon 3 of 6	5		ENSP00000342931.3
POU1F1	ENST00000560656.1 link	c.370A>C	p.Met124Leu	missense_variant	Exon 3 of 4	5		ENSP00000452610.1
POU1F1	ENST00000561167.5 link	c.215-2122A>C		intron_variant	Intron 2 of 4	5		ENSP00000454072.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461734

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727158

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111900

Other (OTH)

AF:

0.00

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Uncertain

0.018

BayesDel_noAF

Benign

-0.21

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.20

T;.;.

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.094

LIST_S2

Benign

0.76

T;T;T

M_CAP

Benign

0.036

MetaRNN

Benign

0.21

T;T;T

MetaSVM

Benign

-0.35

MutationAssessor

Benign

0.34

N;.;.

PhyloP100

7.3

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-0.91

N;N;N

Sift

Benign

0.28

T;T;D

Sift4G

Benign

0.24

T;T;D

Vest4

0.47

ClinPred

0.65

GERP RS

4.5

Varity_R

0.26

gMVP

0.48

Mutation Taster

=69/31

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over