3-87260109-C-T

Variant names:

• chr3-87260109-C-T
• rs76296626
• NM_000306.4:c.666-5G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000306.4(POU1F1):​c.666-5G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00435 in 1,609,948 control chromosomes in the GnomAD database, including 245 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0073 (34 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (211 hom.)
• Consequence: POU1F1 NM_000306.4 splice_region, intron
• Scores: Splicing: ADA: 0.00008690
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.899
• Publications: 2 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 3-87260109-C-T is Benign according to our data. Variant chr3-87260109-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 198069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0797 is higher than 0.05.

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.666-5G>A		splice_region intron	N/A	NP_000297.1	P28069-1
	POU1F1	NM_001122757.3		c.744-5G>A		splice_region intron	N/A	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.666-5G>A		splice_region intron	N/A	ENSP00000263781.2	P28069-1
	POU1F1	ENST00000344265.8	TSL:5	c.744-5G>A		splice_region intron	N/A	ENSP00000342931.3	P28069-2
	POU1F1	ENST00000561167.5	TSL:5	c.441-5G>A		splice_region intron	N/A	ENSP00000454072.1	H0YNM5

Frequencies

GnomAD3 genomes AF: 0.00732 AC: 1107 AN: 151212 Hom.: 34 Cov.: 32

Gnomad AFR AF: 0.00102

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0518

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.0379

Gnomad SAS AF: 0.00209

Gnomad FIN AF: 0.00144

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000575

Gnomad OTH AF: 0.00913

GnomAD2 exomes AF: 0.0154 AC: 3746 AN: 243964 AF XY: 0.0120

Gnomad AFR exome AF: 0.000722

Gnomad AMR exome AF: 0.0836

Gnomad ASJ exome AF: 0.000202

Gnomad EAS exome AF: 0.0409

Gnomad FIN exome AF: 0.00112

Gnomad NFE exome AF: 0.000585

Gnomad OTH exome AF: 0.00962

GnomAD4 exome AF: 0.00404 AC: 5899 AN: 1458620 Hom.: 211 Cov.: 31 AF XY: 0.00361 AC XY: 2620 AN XY: 725518

African (AFR) AF: 0.000688 AC: 23 AN: 33426

American (AMR) AF: 0.0820 AC: 3638 AN: 44390

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26052

East Asian (EAS) AF: 0.0343 AC: 1356 AN: 39560

South Asian (SAS) AF: 0.000744 AC: 64 AN: 85982

European-Finnish (FIN) AF: 0.000921 AC: 49 AN: 53224

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5762

European-Non Finnish (NFE) AF: 0.000432 AC: 479 AN: 1109992

Other (OTH) AF: 0.00470 AC: 283 AN: 60232

GnomAD4 genome AF: 0.00732 AC: 1107 AN: 151328 Hom.: 34 Cov.: 32 AF XY: 0.00830 AC XY: 613 AN XY: 73868

African (AFR) AF: 0.00102 AC: 42 AN: 41206

American (AMR) AF: 0.0518 AC: 786 AN: 15180

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3460

East Asian (EAS) AF: 0.0380 AC: 195 AN: 5128

South Asian (SAS) AF: 0.00209 AC: 10 AN: 4776

European-Finnish (FIN) AF: 0.00144 AC: 15 AN: 10422

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

European-Non Finnish (NFE) AF: 0.000575 AC: 39 AN: 67848

Other (OTH) AF: 0.00903 AC: 19 AN: 2104

Alfa AF: 0.00332 Hom.: 7

Bravo AF: 0.0124

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	2	not specified (2)
-	-	2	Pituitary hormone deficiency, combined, 1 (2)
-	-	1	Combined Pituitary Hormone Deficiency, Recessive (1)
-	-	1	Frontotemporal dementia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	6.9
DANN	Benign	0.90
PhyloP100		0.90
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000087
dbscSNV1_RF	Benign	0.028
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: rs76296626; hg19: chr3-87309259;