NM_000306.4:c.472G>T

Variant names:

• chr3-87262203-C-A
• rs104893756
• NM_000306.4:c.472G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PM5 PP2 PP3_Moderate

The NM_000306.4(POU1F1):​c.472G>T​(p.Ala158Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. A158T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: POU1F1 NM_000306.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.57
• Publications: 7 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: 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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-87262203-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 13604.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.856

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POU1F1	NM_000306.4	c.472G>T	p.Ala158Ser	missense_variant	Exon 4 of 6	ENST00000350375.7	NP_000297.1
POU1F1	NM_001122757.3	c.550G>T	p.Ala184Ser	missense_variant	Exon 4 of 6		NP_001116229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POU1F1	ENST00000350375.7	c.472G>T	p.Ala158Ser	missense_variant	Exon 4 of 6	1	NM_000306.4	ENSP00000263781.2
POU1F1	ENST00000344265.8	c.550G>T	p.Ala184Ser	missense_variant	Exon 4 of 6	5		ENSP00000342931.3
POU1F1	ENST00000561167.5	c.247G>T	p.Ala83Ser	missense_variant	Exon 3 of 5	5		ENSP00000454072.1
POU1F1	ENST00000560656.1	c.439+2085G>T		intron_variant	Intron 3 of 3	5		ENSP00000452610.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T;.;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D;D;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.86	D;D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Benign	1.6	L;.;.
PhyloP100		7.6
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.2	N;N;N
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0050	D;D;D
Sift4G	Uncertain	0.0040	D;D;.
Polyphen		0.97	D;D;.
Vest4		0.80
MutPred		0.67		Gain of disorder (P = 0.0448);.;.;
MVP		0.87
MPC		0.33
ClinPred		0.99	D
GERP RS		6.0
Varity_R		0.72
gMVP		0.56
Mutation Taster		=20/80	disease causing

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: rs104893756; hg19: chr3-87311353;