rs4072924

Variant names:

• chr5-177995822-C-T
• rs4072924
• NM_006261.5:c.109+3G>A

Variant summary

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

The NM_006261.5(PROP1):​c.109+3G>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 0.541 in 1,611,710 control chromosomes in the GnomAD database, including 238,286 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.54 (22452 hom., cov: 34)
  • Exomes 𝑓: 0.54 (215834 hom.)
• Consequence: PROP1 NM_006261.5 splice_region, intron
• Scores: Splicing: ADA: 0.0001374
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.208
• Publications: 20 publications found

Genes affected

PROP1 (HGNC:9455): (PROP paired-like homeobox 1) This gene encodes a paired-like homeodomain transcription factor in the developing pituitary gland. Expression occurs prior to and is required for expression of pou domain transcription factor 1, which is responsible for pituitary development and hormone expression. Mutations in this gene have been associated with combined pituitary hormone deficiency-2 as well as deficiencies in luteinizing hormone, follicle-stimulating hormone, growth hormone, prolactin, and thyroid-stimulating hormone. [provided by RefSeq, Sep 2011]

PROP1 Gene-Disease associations (from GenCC):

• pituitary hormone deficiency, combined, 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Myriad Women’s Health, 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
• panhypopituitarism

  Inheritance: AR 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=-0.47).
• BP6: Variant 5-177995822-C-T is Benign according to our data. Variant chr5-177995822-C-T is described in ClinVar as Benign. ClinVar VariationId is 353016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.568 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006261.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PROP1	NM_006261.5	MANE Select	c.109+3G>A		splice_region intron	N/A	NP_006252.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PROP1	ENST00000308304.2	TSL:1 MANE Select	c.109+3G>A		splice_region intron	N/A	ENSP00000311290.2

Frequencies

GnomAD3 genomes AF: 0.541 AC: 82161 AN: 151998 Hom.: 22441 Cov.: 34

Gnomad AFR AF: 0.574

Gnomad AMI AF: 0.581

Gnomad AMR AF: 0.478

Gnomad ASJ AF: 0.475

Gnomad EAS AF: 0.431

Gnomad SAS AF: 0.422

Gnomad FIN AF: 0.509

Gnomad MID AF: 0.396

Gnomad NFE AF: 0.561

Gnomad OTH AF: 0.503

GnomAD2 exomes AF: 0.507 AC: 127052 AN: 250828 AF XY: 0.503

Gnomad AFR exome AF: 0.578

Gnomad AMR exome AF: 0.437

Gnomad ASJ exome AF: 0.476

Gnomad EAS exome AF: 0.424

Gnomad FIN exome AF: 0.515

Gnomad NFE exome AF: 0.554

Gnomad OTH exome AF: 0.515

GnomAD4 exome AF: 0.541 AC: 789333 AN: 1459594 Hom.: 215834 Cov.: 36 AF XY: 0.537 AC XY: 390082 AN XY: 726232

African (AFR) AF: 0.574 AC: 19201 AN: 33440

American (AMR) AF: 0.442 AC: 19755 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.475 AC: 12416 AN: 26120

East Asian (EAS) AF: 0.380 AC: 15071 AN: 39696

South Asian (SAS) AF: 0.424 AC: 36512 AN: 86198

European-Finnish (FIN) AF: 0.518 AC: 27288 AN: 52720

Middle Eastern (MID) AF: 0.406 AC: 2317 AN: 5706

European-Non Finnish (NFE) AF: 0.562 AC: 624677 AN: 1110668

Other (OTH) AF: 0.532 AC: 32096 AN: 60332

GnomAD4 genome AF: 0.540 AC: 82215 AN: 152116 Hom.: 22452 Cov.: 34 AF XY: 0.534 AC XY: 39731 AN XY: 74360

African (AFR) AF: 0.574 AC: 23810 AN: 41506

American (AMR) AF: 0.478 AC: 7306 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.475 AC: 1649 AN: 3468

East Asian (EAS) AF: 0.431 AC: 2225 AN: 5158

South Asian (SAS) AF: 0.420 AC: 2025 AN: 4824

European-Finnish (FIN) AF: 0.509 AC: 5382 AN: 10570

Middle Eastern (MID) AF: 0.388 AC: 114 AN: 294

European-Non Finnish (NFE) AF: 0.561 AC: 38119 AN: 67980

Other (OTH) AF: 0.500 AC: 1055 AN: 2112

Alfa AF: 0.544 Hom.: 42114

Bravo AF: 0.536

Asia WGS AF: 0.439 AC: 1527 AN: 3478

EpiCase AF: 0.537

EpiControl AF: 0.541

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Pituitary hormone deficiency, combined, 2 (3)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	13
DANN	Benign	0.85
PhyloP100		0.21
PromoterAI		0.076	Neutral
Mutation Taster		=94/6	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00014
dbscSNV1_RF	Benign	0.0
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: rs4072924; hg19: chr5-177422823;