rs143373007

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr3-87264357-T-C
• chr3-87264357-T-G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_000306.4(POU1F1):​c.370A>G​(p.Met124Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0024 in 1,613,976 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (6 hom.)
• Consequence: POU1F1 NM_000306.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:3
• Conservation: PhyloP100: 7.33
• Publications: 3 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: Benign. The variant received -12 ACMG points.

• 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=0.007046312).
• BP6: Variant 3-87264357-T-C is Benign according to our data. Variant chr3-87264357-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 346844.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0018 (274/152246) while in subpopulation NFE AF = 0.0025 (170/68010). AF 95% confidence interval is 0.00219. There are 1 homozygotes in GnomAd4. There are 140 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 6 AD,AR,SD gene

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>G	p.Met124Val	missense	Exon 3 of 6	NP_000297.1
	POU1F1	NM_001122757.3		c.448A>G	p.Met150Val	missense	Exon 3 of 6	NP_001116229.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POU1F1	ENST00000350375.7	TSL:1 MANE Select	c.370A>G	p.Met124Val	missense	Exon 3 of 6	ENSP00000263781.2
	POU1F1	ENST00000344265.8	TSL:5	c.448A>G	p.Met150Val	missense	Exon 3 of 6	ENSP00000342931.3
	POU1F1	ENST00000560656.1	TSL:5	c.370A>G	p.Met124Val	missense	Exon 3 of 4	ENSP00000452610.1

Frequencies

GnomAD3 genomes AF: 0.00180 AC: 274 AN: 152128 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000985

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00593

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00250

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00197 AC: 496 AN: 251286 AF XY: 0.00206

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000665

Gnomad ASJ exome AF: 0.000595

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00550

Gnomad NFE exome AF: 0.00254

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00246 AC: 3594 AN: 1461730 Hom.: 6 Cov.: 31 AF XY: 0.00242 AC XY: 1760 AN XY: 727158

African (AFR) AF: 0.000299 AC: 10 AN: 33476

American (AMR) AF: 0.000850 AC: 38 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000498 AC: 13 AN: 26128

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

South Asian (SAS) AF: 0.00146 AC: 126 AN: 86252

European-Finnish (FIN) AF: 0.00524 AC: 280 AN: 53418

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00267 AC: 2971 AN: 1111896

Other (OTH) AF: 0.00255 AC: 154 AN: 60388

GnomAD4 genome AF: 0.00180 AC: 274 AN: 152246 Hom.: 1 Cov.: 32 AF XY: 0.00188 AC XY: 140 AN XY: 74436

African (AFR) AF: 0.000313 AC: 13 AN: 41568

American (AMR) AF: 0.000983 AC: 15 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4830

European-Finnish (FIN) AF: 0.00593 AC: 63 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00250 AC: 170 AN: 68010

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.00227 Hom.: 3

Bravo AF: 0.00150

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.00185 AC: 224

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00235

EpiControl AF: 0.00261

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	not provided (3)
-	1	1	not specified (2)
-	2	-	Pituitary hormone deficiency, combined, 1 (2)
-	1	-	Combined Pituitary Hormone Deficiency, Recessive (1)
-	-	1	POU1F1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.10
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.096
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.0070	T
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	0.34	N
PhyloP100		7.3
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.79	N
REVEL	Uncertain	0.37
Sift	Benign	0.16	T
Sift4G	Benign	0.19	T
Polyphen		0.0020	B
Vest4		0.53
MVP		0.75
MPC		0.052
ClinPred		0.024	T
GERP RS		4.5
Varity_R		0.20
gMVP		0.60
Mutation Taster		=82/18	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;