rs104893756

Positions:

• chr3-87262203-C-A
• chr3-87262203-C-G
• chr3-87262203-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 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. A158P) has been classified as Pathogenic.

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

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a domain POU-specific (size 74) in uniprot entity PIT1_HUMAN there are 9 pathogenic changes around while only 2 benign (82%) in NM_000306.4
• 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 id is 13604.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.856

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POU1F1	NM_000306.4	c.472G>T	p.Ala158Ser	missense_variant	4/6	ENST00000350375.7
POU1F1	NM_001122757.3	c.550G>T	p.Ala184Ser	missense_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POU1F1	ENST00000350375.7	c.472G>T	p.Ala158Ser	missense_variant	4/6	1	NM_000306.4	P4
POU1F1	ENST00000344265.8	c.550G>T	p.Ala184Ser	missense_variant	4/6	5		A1
POU1F1	ENST00000561167.5	c.247G>T	p.Ala83Ser	missense_variant	3/5	5
POU1F1	ENST00000560656.1	c.439+2085G>T		intron_variant		5

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;.;.
MutationTaster	Benign	1.0	D;D;D
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

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

LitVar

Other links and lift over

dbSNP: rs104893756; hg19: chr3-87311353;