chr3-87259899-T-C

Variant names:

• chr3-87259899-T-C
• rs776355574
• NM_000306.4:c.871A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_000306.4(POU1F1):​c.871A>G​(p.Arg291Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,580 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R291R) 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: 3.19
• 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, SD, AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 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=0.38159937).

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.871A>G	p.Arg291Gly	missense	Exon 6 of 6	NP_000297.1	P28069-1
	POU1F1	NM_001122757.3		c.949A>G	p.Arg317Gly	missense	Exon 6 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.871A>G	p.Arg291Gly	missense	Exon 6 of 6	ENSP00000263781.2	P28069-1
	POU1F1	ENST00000344265.8	TSL:5	c.949A>G	p.Arg317Gly	missense	Exon 6 of 6	ENSP00000342931.3	P28069-2
	POU1F1	ENST00000561167.5	TSL:5	c.646A>G	p.Arg216Gly	missense	Exon 5 of 5	ENSP00000454072.1	H0YNM5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250410 AF XY: 0.00000738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460580 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726706

African (AFR) AF: 0.00 AC: 0 AN: 33448

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.00 AC: 0 AN: 86224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110876

Other (OTH) AF: 0.00 AC: 0 AN: 60348

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.31	T
MetaSVM	Uncertain	0.28	D
MutationAssessor	Benign	0.69	N
PhyloP100		3.2
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	0.77	N
REVEL	Uncertain	0.51
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.36	B
Vest4		0.48
MutPred		0.40		Loss of stability (P = 0.0445)
MVP		0.43
MPC		0.28
ClinPred		0.78	D
GERP RS		4.8
Varity_R		0.71
gMVP		0.51
Mutation Taster		=87/13	polymorphism

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

Other links and lift over

dbSNP: rs776355574; hg19: chr3-87309049;