3-87264357-T-G

Variant names:

• chr3-87264357-T-G
• rs143373007
• NM_000306.4:c.370A>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.33
• Publications: 0 publications found

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: AR, AD, SD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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

ACMG classification

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).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000306.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POU1F1	NM_000306.4	MANE Select	c.370A>C	p.Met124Leu	missense	Exon 3 of 6	NP_000297.1	P28069-1
	POU1F1	NM_001122757.3		c.448A>C	p.Met150Leu	missense	Exon 3 of 6	NP_001116229.1	P28069-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POU1F1	ENST00000350375.7	TSL:1 MANE Select	c.370A>C	p.Met124Leu	missense	Exon 3 of 6	ENSP00000263781.2	P28069-1
	POU1F1	ENST00000344265.8	TSL:5	c.448A>C	p.Met150Leu	missense	Exon 3 of 6	ENSP00000342931.3	P28069-2
	POU1F1	ENST00000560656.1	TSL:5	c.370A>C	p.Met124Leu	missense	Exon 3 of 4	ENSP00000452610.1	H0YK06

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461734 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727158

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111900

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	19
DANN	Benign	0.94
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.094
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	0.34	N
PhyloP100		7.3
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.91	N
REVEL	Benign	0.24
Sift	Benign	0.28	T
Sift4G	Benign	0.24	T
Polyphen		0.0010	B
Vest4		0.47
MutPred		0.51		Gain of glycosylation at S126 (P = 0.0081)
MVP		0.49
MPC		0.050
ClinPred		0.65	D
GERP RS		4.5
Varity_R		0.26
gMVP		0.48
Mutation Taster		=69/31	polymorphism

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

Other links and lift over

dbSNP: rs143373007; hg19: chr3-87313507;