rs1135320

Variant names:

• chr5-177995907-A-G
• rs1135320
• NM_006261.5:c.27T>C

Your query was ambiguous. Multiple possible variants found:

• chr5-177995907-A-G
• chr5-177995907-A-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006261.5(PROP1):​c.27T>C​(p.Ala9Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.452 in 1,613,148 control chromosomes in the GnomAD database, including 168,297 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (14007 hom., cov: 32)
  • Exomes 𝑓: 0.46 (154290 hom.)
• Consequence: PROP1 NM_006261.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -2.04
• Publications: 16 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: Labcorp Genetics (formerly Invitae), G2P, Myriad Women’s Health, Ambry Genetics
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 5-177995907-A-G is Benign according to our data. Variant chr5-177995907-A-G is described in ClinVar as Benign. ClinVar VariationId is 353017.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.04 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.563 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PROP1	NM_006261.5	MANE Select	c.27T>C	p.Ala9Ala	synonymous	Exon 1 of 3	NP_006252.4	O75360

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PROP1	ENST00000308304.2	TSL:1 MANE Select	c.27T>C	p.Ala9Ala	synonymous	Exon 1 of 3	ENSP00000311290.2	O75360

Frequencies

GnomAD3 genomes AF: 0.418 AC: 63531 AN: 151834 Hom.: 13996 Cov.: 32

Gnomad AFR AF: 0.282

Gnomad AMI AF: 0.501

Gnomad AMR AF: 0.508

Gnomad ASJ AF: 0.526

Gnomad EAS AF: 0.568

Gnomad SAS AF: 0.578

Gnomad FIN AF: 0.490

Gnomad MID AF: 0.599

Gnomad NFE AF: 0.439

Gnomad OTH AF: 0.467

GnomAD2 exomes AF: 0.483 AC: 121262 AN: 251114 AF XY: 0.489

Gnomad AFR exome AF: 0.276

Gnomad AMR exome AF: 0.556

Gnomad ASJ exome AF: 0.525

Gnomad EAS exome AF: 0.577

Gnomad FIN exome AF: 0.485

Gnomad NFE exome AF: 0.446

Gnomad OTH exome AF: 0.479

GnomAD4 exome AF: 0.455 AC: 665221 AN: 1461196 Hom.: 154290 Cov.: 50 AF XY: 0.459 AC XY: 334033 AN XY: 726966

African (AFR) AF: 0.279 AC: 9333 AN: 33476

American (AMR) AF: 0.550 AC: 24603 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.526 AC: 13734 AN: 26130

East Asian (EAS) AF: 0.622 AC: 24695 AN: 39698

South Asian (SAS) AF: 0.577 AC: 49743 AN: 86254

European-Finnish (FIN) AF: 0.483 AC: 25646 AN: 53144

Middle Eastern (MID) AF: 0.588 AC: 3392 AN: 5768

European-Non Finnish (NFE) AF: 0.438 AC: 486353 AN: 1111638

Other (OTH) AF: 0.459 AC: 27722 AN: 60370

GnomAD4 genome AF: 0.418 AC: 63579 AN: 151952 Hom.: 14007 Cov.: 32 AF XY: 0.426 AC XY: 31626 AN XY: 74270

African (AFR) AF: 0.282 AC: 11670 AN: 41442

American (AMR) AF: 0.508 AC: 7764 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.526 AC: 1826 AN: 3470

East Asian (EAS) AF: 0.568 AC: 2913 AN: 5128

South Asian (SAS) AF: 0.581 AC: 2796 AN: 4814

European-Finnish (FIN) AF: 0.490 AC: 5167 AN: 10554

Middle Eastern (MID) AF: 0.606 AC: 177 AN: 292

European-Non Finnish (NFE) AF: 0.439 AC: 29818 AN: 67954

Other (OTH) AF: 0.470 AC: 993 AN: 2112

Alfa AF: 0.431 Hom.: 26425

Bravo AF: 0.417

Asia WGS AF: 0.552 AC: 1916 AN: 3478

EpiCase AF: 0.463

EpiControl AF: 0.459

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Pituitary hormone deficiency, combined, 2 (5)
-	-	3	not specified (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	2.6
DANN	Benign	0.14
PhyloP100		-2.0
PromoterAI		0.059	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs1135320; hg19: chr5-177422908; COSMIC: COSV57645313;